ubiquinone and Mitochondrial-Diseases

Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.

Topics: Ataxia; Humans; Lipids; Mitochondrial Diseases; Oxidation-Reduction; Ubiquinone

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

Topics: Ataxia; Cardiomyopathies; Epilepsy; Female; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Pregnancy; Ubiquinone

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.

Topics: Ataxia; Genetic Association Studies; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Steroids; Ubiquinone

Coenzyme Q

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10 (CoQ10) deficiency is broadly divided into two types, primary and secondary. Primary CoQ10 deficiencies are relatively rare disorders resulting from mutations in genes directly involved in the CoQ10 biosynthetic pathway, and are not a subject of this article. Secondary CoQ10 disorders are relatively common, and may occur for a variety of reasons; these include mutations in genes not directly related to the synthetic pathway, oxidative stress induced reduction of CoQ10, and the effects of pharmacological agents such as statins. CoQ10 is of key importance in cell metabolism; in addition to its role in mitochondrial oxidative phosphorylation, it is a major endogenous antioxidant, and has a role in the metabolism of sulphides, lipids and amino acids. Given its importance in cell metabolism, it is unsurprising that secondary CoQ10 deficiency has been linked with a wide range of disorders. In this article, we have reviewed evidence of secondary CoQ10 deficiency in both common and less common disorders, and highlighted those disorders in which CoQ10 supplementation has been shown to be of significant clinical benefit.

Topics: Dietary Supplements; Humans; Mitochondria; Mitochondrial Diseases; Ubiquinone

Coenzyme Q10 (ubiquinone or CoQ10) is a lipid molecule that acts as an electron mobile carrier of the electron transport chain and also contains antioxidant properties. Supplementation of CoQ10 has been very useful to treat mitochondrial diseases. CoQ10 along with its synthetic analogue, idebenone, is used largely to treat various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Friedreich's ataxia and additional brain disease condition like autism, multiple sclerosis, epilepsy, depression, and bipolar disorder, which are related to mitochondrial impairment. In this article, we have reviewed numerous physiological functions of CoQ10 and the rationale for its use in clinical practice in different brain disorders.

Topics: Animals; Antioxidants; Brain Diseases; Humans; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Ubiquinone

Primary coenzyme Q

Topics: Ataxia; Exome; Exome Sequencing; Genome; High-Throughput Nucleotide Sequencing; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Saccharomyces cerevisiae; Ubiquinone; Whole Genome Sequencing

Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in all cell membranes, limiting the toxic effect of free radicals, it is a component of LDL, it is involved in the aging process, and its deficiency is linked to several diseases. Recently, it has been proposed that coenzyme Q contributes to suppressing ferroptosis, a type of iron-dependent programmed cell death characterized by lipid peroxidation. In this review, we report the latest hypotheses and theories analyzing the multiple functions of coenzyme Q. The complete knowledge of the various cellular CoQ functions is essential to provide a rational basis for its possible therapeutic use, not only in diseases characterized by primary CoQ deficiency, but also in large number of diseases in which its secondary deficiency has been found.

Topics: Animals; Ataxia; Cell Membrane; Cell Respiration; Humans; Lipid Peroxidation; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).

Topics: Animals; Antioxidants; Electron Transport; Humans; Mitochondria; Mitochondrial Diseases; Nervous System Diseases; Ubiquinone

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria, and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases, including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in people with heart failure, and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels, and in preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to people with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials was conducted prior to the original version of this Cochrane Review, in 2014.. To review the safety and efficacy of coenzyme Q10 in heart failure.. We searched CENTRAL, MEDLINE, Embase, Web of Science, CINAHL Plus, and AMED on 16 October 2020; ClinicalTrials.gov on 16 July 2020, and the ISRCTN Registry on 11 November 2019. We applied no language restrictions.. We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in people with heart failure. When we identified cross-over studies, we considered data only from the first phase.. We used standard Cochrane methods, assessed study risk of bias using the Cochrane 'Risk of bias' tool, and GRADE methods to assess the quality of the evidence. For dichotomous data, we calculated the risk ratio (RR); for continuous data, the mean difference (MD), both with 95% confidence intervals (CI). Where appropriate data were available, we conducted meta-analysis. When meta-analysis was not possible, we wrote a narrative synthesis. We provided a PRISMA flow chart to show the flow of study selection.. We included eleven studies, with 1573 participants, comparing coenzyme Q10 to placebo or conventional therapy (control). In the majority of the studies, sample size was relatively small. There were important differences among studies in daily coenzyme Q10 dose, follow-up period, and the measures of treatment effect. All studies had unclear, or high risk of bias, or both, in one or more bias domains. We were only able to conduct meta-analysis for some of the outcomes. None of the included trials considered quality of life, measured on a validated scale, exercise variables (exercise haemodynamics), or cost-effectiveness. Coenzyme Q10 probably reduces the risk of all-cause mortality more than control (RR 0.58, 95% CI 0.35 to 0.95; 1 study, 420 participants; number needed to treat for an additional beneficial outcome (NNTB) 13.3; moderate-quality evidence). There was low-quality evidence of inconclusive results between the coenzyme Q10 and control groups for the risk of myocardial infarction (RR 1.62, 95% CI 0.27 to 9.59; 1 study, 420 participants), and stroke (RR 0.18, 95% CI 0.02 to 1.48; 1 study, 420 participants). Coenzyme Q10 probably reduces hospitalisation related to heart failure (RR 0.62, 95% CI 0.49 to 0.78; 2 studies, 1061 participants; NNTB 9.7; moderate-quality evidence). Very low-quality evidence suggests that coenzyme Q10 may improve the left ventricular ejection fraction (MD 1.77, 95% CI 0.09 to 3.44; 7 studies, 650 participants), but the results are inconclusive for exercise capacity (MD 48.23, 95% CI -24.75 to 121.20; 3 studies, 91 participants); and the risk of developing adverse events (RR 0.70, 95% CI 0.45 to 1.10; 2 studies, 568 participants). We downgraded the quality of the evidence mainly due to high risk of bias and imprecision.. The included studies provide moderate-quality evidence that coenzyme Q10 probably reduces all-cause mortality and hospitalisation for heart failure. There is low-quality evidence of inconclusive results as to whether coenzyme Q10 has an effect on the risk of myocardial infarction, or stroke. Because of very low-quality evidence, it is very uncertain whether coenzyme Q10 has an effect on either left ventricular ejection fraction or exercise capacity. There is low-quality evidence that coenzyme Q10 may increase the risk of adverse effects, or have little to no difference. There is currently no convincing evidence to support or refute the use of coenzyme Q10 for heart failure. Future trials are needed to confirm our findings.

Topics: Ataxia; Heart Failure; Humans; Mitochondrial Diseases; Muscle Weakness; Myocardial Infarction; Quality of Life; Stroke; Stroke Volume; Ubiquinone; Ventricular Function, Left

Coenzyme Q

Topics: Ataxia; Cardiovascular Diseases; Dietary Supplements; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis and demise. An increasingly higher number of pathologies is linked with mitochondrial dysfunction, which can arise from either genetic defects affecting core mitochondrial components or malfunctioning pathways impairing mitochondrial homeostasis. As such, mitochondria are considered an important target in several pathologies spanning from neoplastic to neurodegenerative diseases as well as metabolic syndromes. In this review we provide an overview of the state-of-the-art in mitochondrial pharmacology, focusing on the novel compounds that have been generated in the bid to correct mitochondrial aberrations. Our work aims to serve the scientific community working on translational medical science by highlighting the most promising pharmacological approaches to target mitochondrial dysfunction in disease.

Topics: Antioxidants; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Neurodegenerative Diseases; Oxidative Phosphorylation; Pyrazines; Ubiquinone

Coenzyme Q (CoQ) is a redox active lipid that plays a central role in cellular homeostasis. It was discovered more than 60 years ago because of its role as electron transporter in the mitochondrial respiratory chain. Since then it has become evident that CoQ has many other functions, not directly related to bioenergetics. It is a cofactor of several mitochondrial dehydrogenases involved in the metabolism of lipids, amino acids, and nucleotides, and in sulfide detoxification. It is a powerful antioxidant and it is involved in the control of programmed cell death by modulating both apoptosis and ferroptosis. CoQ deficiency is a clinically and genetically heterogeneous group of disorders characterized by the impairment of CoQ biosynthesis. CoQ deficient patients display defects in cellular bioenergetics, but also in the other pathways in which CoQ is involved. In this review we will focus on the functions of CoQ not directly related to the respiratory chain, and on how their impairment is relevant for the pathophysiology of CoQ deficiency. A better understanding of the complex set of events triggered by CoQ deficiency will allow to design novel approaches for the treatment of this condition.

Topics: Ataxia; Homeostasis; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Primary Coenzyme Q (CoQ) deficiencies are clinically heterogeneous conditions and lack clear genotype-phenotype correlations, complicating diagnosis and prognostic assessment. Here we present a compilation of all the symptoms and patients with primary CoQ deficiency described in the literature so far and analyse the most common clinical manifestations associated with pathogenic variants identified in the different COQ genes. In addition, we identified new associations between the age of onset of symptoms and different pathogenic variants, which could help to a better diagnosis and guided treatment. To make these results useable for clinicians, we created an online platform (https://coenzymeQbiology.github.io/clinic-CoQ-deficiency) about clinical manifestations of primary CoQ deficiency that will be periodically updated to incorporate new information published in the literature. Since CoQ primary deficiency is a rare disease, the available data are still limited, but as new patients are added over time, this tool could become a key resource for a more efficient diagnosis of this pathology.

Topics: Ataxia; Genetic Association Studies; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q

Topics: Aging; Alkyl and Aryl Transferases; Animals; Ataxia; Energy Metabolism; Gene Expression Regulation; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Signal Transduction; Ubiquinone

Coenzyme Q

Topics: Aging; Ataxia; Cardiovascular Diseases; Dietary Supplements; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Ubiquinone

Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease.

Topics: Antioxidants; Ataxia; Humans; Inflammation; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H

Topics: Animals; Ataxia; Brain; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Retina; Ubiquinone

Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q

Topics: Adult; Aging; Animals; Antioxidants; Ataxia; Caenorhabditis elegans; Diet; Female; Hormesis; Humans; Male; Mice; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Rats; Ubiquinone; Young Adult

Ubiquinone (UQ, coenzyme Q) is an essential electron transfer lipid in the mitochondrial respiratory chain. It is a main source of mitochondrial reactive oxygen species (ROS) but also has antioxidant properties. This mix of characteristics is why ubiquinone supplementation is considered a potential therapy for many diseases involving mitochondrial dysfunction. Mutations in the ubiquinone biosynthetic pathway are increasingly being identified in patients. Furthermore, secondary ubiquinone deficiency is a common finding associated with mitochondrial disorders and might exacerbate these conditions. Recent developments have suggested that ubiquinone biosynthesis occurs in discrete domains of the mitochondrial inner membrane close to ER-mitochondria contact sites. This spatial requirement for ubiquinone biosynthesis could be the link between secondary ubiquinone deficiency and mitochondrial dysfunction, which commonly results in loss of mitochondrial structural integrity.

Topics: Animals; Endoplasmic Reticulum; Humans; Mitochondria; Mitochondrial Diseases; Reactive Oxygen Species; Ubiquinone

Cerebellar ataxia is a hallmark of coenzyme Q

Topics: Adult; Ataxia; Child; Disease Progression; Dystonic Disorders; Female; Handwriting; Heterozygote; Humans; Male; Middle Aged; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Ubiquinone; Young Adult

Mitochondrial function is closely linked to numerous aspects of eye health. Imbalance between the creation of energy and the development of reactive oxygen species (ROS) seems to be the cause of the development of mitochondrial dysfunctions. As a result of this energy deficit, the level of oxidative stress in the eye tissues increases, leading to numerous ophthalmic impairments. It is important to distinguish between primary mitochondrial eye diseases and secondary mitochondrial changes. Primary mitochondrial eye diseases, for example Leber's hereditary optic atrophy (LHON), retinitis pigmentosa and chronic progressive external ophthalmoplegia are caused by direct damage to mitochondrial function induced by defective genes, either located on mitochondrial DNA (mtDNA) or the DNA of the nucleus (nDNA). In contrast, secondary mitochondrial dysfunctions are caused by environmental factors. In recent years, there has been growing evidence that mitochondrial dysfunctions play an important role in many common eye diseases, such as glaucoma, dry eye, diabetic retinopathy, cataract and age-related macular degeneration (AMD). This article summarises current knowledge of mitochondrial dysfunctions and the role of coenzyme Q10 (CoQ10) as a possible treatment option - with a special focus on glaucoma.. Die mitochondriale Funktion ist mit zahlreichen Aspekten der Gesundheit des Auges eng verknüpft. Ursächlich für mitochondriale Dysfunktionen scheint ein Ungleichgewicht zwischen der Bildung von Energie und der Menge an freien Radikalen zu sein. Dadurch kommt es neben einem Energiemangel zu einer erhöhten oxidativen Belastung der betroffenen Augengewebe mit der Folge einer Vielzahl von ophthalmologischen Beeinträchtigungen. Dabei wird zwischen primären und sekundären mitochondrialen Augenerkrankungen unterschieden. Primäre mitochondriale Erkrankungen wie bspw. die Leberʼsche hereditäre Optikusatrophie (LHON), die Retinitis pigmentosa und die chronisch progressive externe Ophthalmoplegie sind die Folge von direkten Schädigungen der mitochondrialen Funktion durch defekte Gene auf der mitochondrialen DNA (mtDNA) oder auf der nukleären DNA (nDNA). Demgegenüber sind sekundäre mitochondriale Dysfunktionen vor allem auf Umwelteinflüsse zurückzuführen. In jüngster Zeit häufen sich Hinweise darauf, dass auch mitochondriale Dysfunktionen bei vielen häufig auftretenden Augenerkrankungen wie dem Glaukom, dem „Trockenen Auge“, der diabetischen Retinopathie, der Katarakt und der altersabhängigen Makuladegeneration (AMD) eine wichtige Rolle spielen. Dieser Beitrag fasst den derzeitigen Kenntnisstand zu mitochondrialen Dysfunktionen und zur Rolle von Coenzym Q10 (CoQ10) als mögliche Therapieoption beim Glaukom zusammen.

Topics: Animals; Biological Availability; Diagnosis, Differential; Disease Models, Animal; Electron Transport; Energy Metabolism; Eye; Free Radicals; Glaucoma; Humans; Microscopy, Electron; Mitochondrial Diseases; Ophthalmic Solutions; Reactive Oxygen Species; Risk Factors; Ubiquinone

Coenzyme Q

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Pathology, Molecular; Ubiquinone

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway.

Topics: Ataxia; Genes, Fungal; Genome, Human; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Models, Biological; Muscle Weakness; Mutation; Parabens; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Primary Coenzyme Q deficiencies represent a group of rare conditions caused by mutations in one of the genes required in its biosynthetic pathway at the enzymatic or regulatory level. The associated clinical manifestations are highly heterogeneous and mainly affect central and peripheral nervous system, kidney, skeletal muscle and heart. Genotype-phenotype correlations are difficult to establish, mainly because of the reduced number of patients and the large variety of symptoms. In addition, mutations in the same

Topics: Ataxia; Genotype; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Structure-Activity Relationship; Syndrome; Ubiquinone

Atherothrombosis is a recurrent complication in APS and SLE patients. Oxidative stress has been suggested as a key player underlying this process. Autoantibodies have been pointed to as the main contributors to abnormality in the oxidative status observed in APS and SLE patients, promoting the increased production of oxidant species and the reduction of antioxidant molecules. This imbalance causes vascular damage through the activation of immune cells, including monocytes, lymphocytes and neutrophils, causing the expression of pro-inflammatory and procoagulant molecules, the formation of neutrophil extracellular traps and the adhesion of these cells to the endothelium; the induction of cellular apoptosis and impaired cell clearance, which in turn enhances autoantibody neogeneration; and cytotoxicity of endothelial cells. This review describes the mechanisms underlying the role of oxidative stress in the pathogenesis of atherothrombosis associated with APS and SLE, focused on the effect of autoantibodies, the different cell types involved and the diverse effectors, including cytokines, procoagulant proteins and their main modulators, such as oxidant/antioxidant species and intracellular pathways in each pathology. We further discuss new therapies aimed at restoring the oxidative stress balance and subsequently to tackle atherothrombosis in APS and SLE.

Topics: Acetylcysteine; Anticoagulants; Antioxidants; Antiphospholipid Syndrome; Atherosclerosis; Autoantibodies; beta 2-Glycoprotein I; Coagulants; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lupus Erythematosus, Systemic; Mitochondrial Diseases; Oxidative Stress; Reactive Oxygen Species; Recurrence; Thrombosis; Ubiquinone

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Topics: Adenosine Triphosphate; Animals; Ataxia; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Protein Multimerization; Reactive Oxygen Species; Saccharomyces cerevisiae; Ubiquinone

In recent years, the analytical determination of coenzyme Q10 (CoQ10) has gained importance in clinical diagnosis and in pharmaceutical quality control. CoQ10 is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases and patients with these conditions may benefit from administration of supplements of CoQ10. In this regard, it has been observed that the best benefits are obtained when CoQ10 deficiency is diagnosed and treated early. Therefore, it is of great value to develop analytical methods for the detection and quantification of CoQ10 in this type of disease. The methods above mentioned should be simple enough to be used in routine clinical laboratories as well as in quality control of pharmaceutical formulations containing CoQ10. Here, we discuss the advantages and disadvantages of different methods of CoQ10 analysis.

Topics: Ataxia; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Humans; Mitochondrial Diseases; Muscle Weakness; Pharmaceutical Preparations; Spectrophotometry; Ubiquinone

Coenzyme Q

Topics: Adult; Aged; Ataxia; Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Collectins; Cross-Sectional Studies; Female; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Nerve Degeneration; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Neurons; Polymorphism, Single Nucleotide; Receptors, Scavenger; Ubiquinone

Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.

Topics: Adenosine Triphosphate; Animals; Ataxia; Central Nervous System Diseases; Disease Models, Animal; Electron Transport; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidative Stress; Phenotype; Ubiquinone

A short review is given of the potential role of selenium deficiency and selenium intervention trials in atherosclerotic heart disease. Selenium is an essential constituent of several proteins, including the glutathione peroxidases and selenoprotein P. The selenium intake in Europe is generally in the lower margin of recommendations from authorities. Segments of populations in Europe may thus have a deficient intake that may be presented by a deficient anti-oxidative capacity in various illnesses, in particular atherosclerotic disease, and this may influence the prognosis of the disease. Ischemic heart disease and heart failure are two conditions where increased oxidative stress has been convincingly demonstrated. Some of the intervention studies of anti-oxidative substances that have focused on selenium are discussed in this review. The interrelationship between selenium and coenzyme Q10, another anti-oxidant, is presented, pointing to a theoretical advantage in using both substances in an intervention if there are deficiencies within the population. Clinical results from an intervention study using both selenium and coenzyme Q10 in an elderly population are discussed, where reduction in cardiovascular mortality, a better cardiac function according to echocardiography, and finally a lower concentration of the biomarker NT-proBNP as a sign of lower myocardial wall tension could be seen in those on active treatment, compared to placebo.

Topics: Animals; Antioxidants; Ataxia; Cardiovascular Diseases; Coronary Artery Disease; Deficiency Diseases; Diet; Dietary Supplements; Europe; Humans; Mitochondrial Diseases; Muscle Weakness; Nutritional Status; Oxidative Stress; Selenium; Ubiquinone

Coenzyme Q10 (CoQ) deficiency syndromes comprise a growing number of neurological and extraneurological disorders. Primary-genetic but also secondary CoQ deficiencies have been reported. The biochemical determination of CoQ is a good tool for the rapid identification of CoQ deficiencies but does not allow the selection of candidate genes for molecular diagnosis. Moreover, the metabolic pathway for CoQ synthesis is an intricate and not well-understood process, where a large number of genes are implicated. Thus, only next-generation sequencing techniques (either genetic panels of whole-exome and -genome sequencing) are at present appropriate for a rapid and realistic molecular diagnosis of these syndromes. The potential treatability of CoQ deficiency strongly supports the necessity of a rapid molecular characterization of patients, since primary CoQ deficiencies may respond well to CoQ treatment.

Topics: Ataxia; Humans; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Ubiquinone; Yeasts

Oxidative phosphorylation (OXPHOS) is a metabolic pathway that uses energy released by the oxidation of nutrients to generate adenosine triphosphate (ATP). Coenzyme Q10 (CoQ10), also known as ubiquinone, plays an essential role in the human body not only by generating ATP in the mitochondrial respiratory chain but also by providing protection from reactive oxygen species (ROS) and functioning in the activation of many mitochondrial dehydrogenases and enzymes required in pyrimidine nucleoside biosynthesis. The presentations of primary CoQ10 deficiencies caused by genetic mutations are very heterogeneous. The phenotypes related to energy depletion or ROS production may depend on the content of CoQ10 in the cell, which is determined by the severity of the mutation. Primary CoQ10 deficiency is unique among mitochondrial disorders because early supplementation with CoQ10 can prevent the onset of neurological and renal manifestations. In this review I summarize primary CoQ10 deficiencies caused by various genetic abnormalities, emphasizing its nephropathic form.

Topics: Ataxia; Humans; Kidney Diseases; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to patients with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials has been conducted.. To review the safety and efficacy of coenzyme Q10 in heart failure.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions.. We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in patients with heart failure. When cross-over studies were identified, we considered data only from the first phase.. Two authors independently extracted data from the included studies onto a pre-designed data extraction form. We then entered the data into Review Manager 5.2 for analysis. We assessed study risk of bias using the Cochrane 'Risk of bias' tool. For dichotomous data, we calculated the risk ratio and for continuous data the mean difference (MD). Where appropriate data were available, we performed meta-analysis. For this review we prioritised data from pooled analyses only. Where meta-analysis was not possible, we wrote a narrative synthesis. We provided a QUOROM flow chart to show the flow of papers.. We included seven studies with 914 participants comparing conenzyme Q10 versus placebo. There were no data on clinical events from published randomised trials. The included studies had small sample sizes. Meta-analysis was only possible for a few physiological measures and there was substantial heterogeneity.Only one study reported on total mortality, major cardiovascular events and hospitalisation. Five trials reported on the New York Heart Association (NYHA) classification of clinical status, but it was impossible to pool data due to heterogeneity. None of the included trials considered quality of life, exercise variables, adverse events or cost-effectiveness as outcome measures. Pooled analysis suggests that the use of coenzyme Q10 has no clear effect on left ventricular ejection fraction (MD -2.26; 95% confidence interval (CI) -15.49 to 10.97, n = 60) or exercise capacity (MD 12.79; 95% CI -140.12 to 165.70, n = 85). Pooled data did indicate that supplementation increased blood levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72, n = 112). However, there are only a small number of small studies with a risk of bias, so these results should be interpreted with caution.. No conclusions can be drawn on the benefits or harms of coenzyme Q10 in heart failure at this time as trials published to date lack information on clinically relevant endpoints. Furthermore, the existing data are derived from small, heterogeneous trials that concentrate on physiological measures: their results are inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable.

Topics: Ataxia; Heart Failure; Humans; Mitochondrial Diseases; Muscle Weakness; Randomized Controlled Trials as Topic; Stroke Volume; Ubiquinone; Vitamins

Neurodegenerative movement disorders mainly include Parkinson's disease (PD), atypical parkinsonisms, Huntington's disease (HD), and Friedreich's ataxia (FA). With mitochondrial dysfunction observed in these diseases, mitochondrial enhancement such as creatine, coenzyme Q10 (CoQ10) and its analogues (idebenone and mitoquinone) has been regarded as a potential treatment.. In this paper, we systematically analysed and summarized the efficacy of mitochondrial enhancement in improving motor and other symptoms in neurodegenerative movement disorders.. We searched the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure until September 2013 for eligible randomized controlled trials (RCTs), as well as unpublished and ongoing trials. We calculated the mean differences for continuous data with 95% confidence intervals and pooled the results using a fixed-effect model, if no significant statistical heterogeneity was found (I(2) < 50%).. We included 16 studies with 1,557 randomized patients, which compared creatine, CoQ10 or its analogues with placebo in motor and other symptoms. No significant improvements were found in the motor symptoms of PD, atypical parkinsonisms or HD patients, while only the high dose of idebenone seems to be promising for motor improvement in FA. Certain benefits are found in other symptoms.. There is insufficient evidence to support the use of mitochondrial enhancement in patients with neurodegenerative movement disorders. More well-designed RCTs with large samples are required for further confirmation.

Topics: Animals; Creatine; Dose-Response Relationship, Drug; Humans; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Ubiquinone

Coenzyme Q, or ubiquinone, is an endogenously synthesized lipid-soluble antioxidant that plays a major role in the mitochondrial respiratory chain. Although extensively studied for decades, recent data on coenzyme Q have painted an exciting albeit incomplete picture of the multiple facets of this molecule's function. In humans, mutations in the genes involved in the biosynthesis of coenzyme Q lead to a heterogeneous group of rare disorders, with most often severe and debilitating symptoms. In this review, we describe the current understanding of coenzyme Q biosynthesis, provide a detailed overview of human coenzyme Q deficiencies and discuss the existing mouse models for coenzyme Q deficiency. Furthermore, we briefly examine the current state of affairs in non-mitochondrial coenzyme Q functions and the latter's link to statin.

Topics: Animals; Ataxia; Disease Models, Animal; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Treatment of mitochondrial respiratory chain (MRC) disorders is extremely difficult, however, coenzyme Q10 (CoQ10) and its synthetic analogues are the only agents which have shown some therapeutic benefit to patients. CoQ10 serves as an electron carrier in the MRC as well as functioning as a potent lipid soluble antioxidant. CoQ10 supplementation is fundamental to the treatment of patients with primary defects in the CoQ10 biosynthetic pathway. The efficacy of CoQ10 and its analogues in the treatment of patients with MRC disorders not associated with a CoQ10 deficiency indicates their ability to restore electron flow in the MRC and/or increase mitochondrial antioxidant capacity may also be important contributory factors to their therapeutic potential.

Topics: Animals; Ataxia; Humans; Mitochondrial Diseases; Molecular Structure; Muscle Weakness; Treatment Outcome; Ubiquinone

Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.

Topics: Brain; Electron Transport Chain Complex Proteins; Genetic Association Studies; Humans; Magnetic Resonance Imaging; Mitochondrial Diseases; Neuroimaging; Ubiquinone

Mitochondrial respiratory chain defects (RCD) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent during the evolution of mitochondrial disorders (30%) with different presentation in childhood and adulthood in term of type of epilepsy, of efficacy of treatment and also in term of prognosis.. Mitochondrial disorders can begin at any age but the diseases with early onset during childhood have generally severe or fatal outcome in few years. Four age-related epileptic phenotypes could be identified in infancy: infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua and myoclonic epilepsy. Except for infantile spasms, epilepsy is difficult to control in most cases (95%). In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. Ketogenic diet could be an interesting alternative treatment in case of recurrent status epilepticus or pharmacoresistant epilepsy.. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death.

Topics: Adult; Ataxia; Child; Diffuse Cerebral Sclerosis of Schilder; DNA Polymerase gamma; DNA-Directed DNA Polymerase; Epilepsy; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Ubiquinone

Topics: Alkyl and Aryl Transferases; Child; DNA, Mitochondrial; Fibroblasts; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Mitochondrial Diseases; Mutation; Nephrotic Syndrome; Protein Kinases; Ubiquinone

Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

Topics: Ataxia; Cerebellar Ataxia; Child; Chronic Disease; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Spinocerebellar Degenerations; Ubiquinone

Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

Topics: Adrenal Cortex Hormones; Ataxia; Cerebellar Ataxia; Chronic Disease; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondrial Diseases; Muscle Weakness; Ubiquinone; Vitamin E; Vitamin E Deficiency

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

Topics: Antioxidants; Arginine; Clinical Trials as Topic; Creatine; Exercise Therapy; Humans; Mitochondrial Diseases; Ubiquinone

Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).. Here, we describe clinical and molecular features of CoQ(10) deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ(10) deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ(10) biosynthesis, often improve with CoQ(10) supplementation. In vitro and in vivo studies of CoQ(10) deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ(10) deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE.. CoQ(10) deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules.. Studies of CoQ(10) deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010.

Topics: Humans; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Thymidine Phosphorylase; Ubiquinone

Topics: Adenosine Triphosphate; Cyclosporine; Enzyme Replacement Therapy; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype; Ubiquinone

Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. The first review was carried out in 2003, and identified six clinical trials. This major update was carried out to identify new studies and grade the original studies for potential bias in accordance with revised Cochrane Collaboration guidelines.. To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease.. We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2, MEDLINE (1966 to July 2011), and EMBASE (January 1980 to July 2011), and contacted experts in the field.. We included randomised controlled trials (including cross-over studies). Two of the authors independently selected abstracts for further detailed review. Further review was performed independently by all five authors to decide which trials fit the inclusion criteria and graded risk of bias. Participants included males and females of any age with a confirmed diagnosis of mitochondrial disease based upon muscle histochemistry, respiratory chain complex analysis of tissues or cell lines or DNA studies. Interventions included any pharmacological agent, dietary modification, nutritional supplement, exercise therapy or other treatment. The review authors excluded studies at high risk of bias in any category. The primary outcome measures included an change in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes.. Two of the authors (GP and PFC) independently identified studies for further evaluation from all abstracts within the search period. For those studies identified for further review, all five authors then independently assessed which studies met the entry criteria. For the included studies, we extracted details of the number of randomised participants, treatment, study design, study category, allocation concealment and other risk of bias criteria, and participant characteristics. Analysis was based on intention-to-treat data. We planned to use meta-analysis, but this did not prove necessary.. The authors reviewed 1335 abstracts, and from these identified 21 potentially eligible abstracts. Upon detailed review, 12 studies fulfilled the entry criteria. Of these, eight were new studies that had been published since the previous version of this review. Two studies which were included in the previous version of this review were excluded because of potential for bias. The comparability of the included studies is extremely low because of differences in the specific diseases studied, differences in the therapeutic agents used, dosage, study design, and outcomes. The methodological quality of included studies was generally high, although risk of bias was unclear in random sequence generation and allocation concealment for most studies. Otherwise, the risk of bias was low for most studies in the other categories. Serious adverse events were uncommon, except for peripheral nerve toxicity in a long-term trial of dichloroacetate (DCA) in adults.One trial studied high-dose coenzyme Q10 without clinically meaningful improvement (although there were multiple biochemical, physiologic, and neuroimaging outcomes, in 30 participants). Three trials used creatine monohydrate alone, with one reporting evidence of improved measures of muscle strength and post-exercise lactate, but the other two reported no benefit (total of 38 participants). One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid and reported a statistically significant improvement in biochemical markers and peak ankle dorsiflexion strength, but overall no clinical improvement in 16 participants. Five trials studied the effects of DCA: three trials in children showed a statistically significant improvement in secondary outcome measures of mitochondrial metabolism (venous lactate in three trials, and magnetic resonance spectroscopy (MRS) in one trial; total of 63 participants). One trial of short-term DCA in adults demonstrated no clinically relevant improvement (improved venous lactate but no change in physiologic, imaging, or questionnaire findings, in eight participants). One longer-term DCA trial in adults was terminated prematurely due to peripheral nerve toxicity without clinical benefit (assessments included the GATE score, venous lactate and MRS, in 30 participants). One trial using dimethylglycine showed no significant effect (measurements of venous lactate and oxygen consumption (VO(2)) in five participants). One trial using a whey-based suppleme. Despite identifying eight new trials there is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches. We suggest further research should identify novel agents to be tested in homogeneous study populations with clinically relevant primary endpoints.

Topics: Creatine; Dichloroacetic Acid; Humans; Mitochondrial Diseases; Randomized Controlled Trials as Topic; Sarcosine; Thioctic Acid; Ubiquinone

Fatigue and exercise intolerance are common symptoms of mitochondrial diseases, but difficult to be clinically assessed. New methods to quantify these rather common complaints are strongly needed in the clinical practice. Coenzyme Q10 administration and aerobic exercise may improve exercise intolerance, but more definite studies are still pending. Herein, we have revised "how to measure" and "how to treat" these symptoms of mitochondrial patients. Subsequently, we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the Italian nation-wide database of mitochondrial disease, with special regard to exercise intolerance. We observed that more of 20% of mitochondrial patients complain of exercise intolerance. This symptom seems to be frequently associated with specific patient groups and/or genotypes. Ragged red fibers and COX-negative fibers are more often present in subjects with exercise intolerance, whereas lactate levels could not predict this symptom. Multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases, and may represent the basis for more rigorous longitudinal studies.

Topics: Exercise; Fatigue; Humans; Mitochondrial Diseases; Mutation; Ubiquinone

Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.

Topics: Animals; Humans; Micronutrients; Mitochondria; Mitochondrial Diseases; Molecular Targeted Therapy; Neurodegenerative Diseases; Ubiquinone

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.

Topics: Animals; Creatine; Disease Models, Animal; Humans; Huntington Disease; Metabolic Diseases; Mitochondrial Diseases; Nerve Tissue; Ubiquinone

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes.

Topics: Animals; Blood Glucose; Cell Respiration; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electron Transport; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Rats; Reactive Oxygen Species; Superoxides; Ubiquinone

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.

Topics: Animals; Humans; Mitochondrial Diseases; Neurodegenerative Diseases; Neuromuscular Diseases; Ubiquinone

While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy. Arginine also has been used to treat MELAS with promising effects, although a controlled trial is still needed for this potentially toxic agent. The anti-oxidant coenzyme Q(10) is very widely used for primary mitochondrial disorders but has not yet undergone a controlled clinical trial; such a trial is now underway, as well as trials of the co-Q analogue idebenone for MELAS and LHON. Greater experience has accumulated with multi-center trials of coenzyme Q(10) treatment to prevent the progression of Parkinson disease. Although initial smaller trials indicated a benefit, this has not yet been confirmed in subsequent trials with higher doses; a larger Phase III trial is now underway. Similarly, a series of trials of idebenone for Friedreich ataxia have shown some benefit in slowing the progression of cardiomyopathy, and controlled clinical trials are now underway to determine if there is significant neurological protection. Uncontrolled trials of exercise showed an increase of exercise tolerance in patients with disorders of mitochondrial DNA, but did not selectively increase the percentage of normal mtDNA; a larger partially controlled trial is now underway to evaluate this possible benefit. In summary, none of the controlled trials so far has conclusively shown a benefit of treatment with the agents tested, but some promising therapies are currently being evaluated in a controlled manner. These experiences underscore the importance of controlled clinical trials for evaluation of benefits and risks of recommended therapies. Application of such clinical trials to future more effective therapies for mitochondrial disorders will require multi-center collaboration, organization, leadership, and financial and advocacy support.

Topics: Arginine; Clinical Trials as Topic; Dichloroacetic Acid; Humans; Mitochondrial Diseases; Randomized Controlled Trials as Topic; Treatment Outcome; Ubiquinone

In addition to its role as a component of the mitochondrial respiratory chain and our only lipid-soluble antioxidant synthesized endogenously, in recent years coenzyme Q (CoQ) has been found to have an increasing number of other important functions required for normal metabolic processes. A number of genetic mutations that reduce CoQ biosynthesis are associated with serious functional disturbances that can be eliminated by dietary administration of this lipid, making CoQ deficiencies the only mitochondrial diseases which can be successfully treated at present. In connection with certain other diseases associated with excessive oxidative stress, the level of CoQ is elevated as a protective response. Aging, certain experimental conditions and several human diseases reduce this level, resulting in serious metabolic disturbances. Since dietary uptake of this lipid is limited, up-regulation of its biosynthetic pathway is of considerable clinical interest. One approach for this purpose is administration of epoxidated all-trans polyisoprenoids, which enhance both CoQ biosynthesis and levels in experimental systems.

Topics: Aging; Humans; Mevalonic Acid; Mitochondria; Mitochondrial Diseases; Ubiquinone

Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins, occurs most frequently and originates from mutations in either the nuclear DNA, encoding 38 structural subunits and several assembly factors, or the mitochondrial DNA, encoding 7 structural subunits. The deficiency is associated with devastating multisystemic disorders, often affecting the brain, with onset in early childhood. There are currently no rational treatment strategies. Here, we present an overview of the genetic origins and cellular consequences of this deficiency and discuss how these insights might aid future development of treatment strategies.

Topics: Antioxidants; Child; Child, Preschool; Developmental Disabilities; Disease Progression; Drug Delivery Systems; Electron Transport Complex I; Energy Metabolism; Humans; Infant; Infant, Newborn; Mitochondrial Diseases; Organophosphorus Compounds; Oxidative Phosphorylation; Plastoquinone; Resveratrol; Stilbenes; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies.

Topics: Atrophy; Cerebellum; Child; Chromosome Aberrations; Developmental Disabilities; Disease Progression; DNA Mutational Analysis; Genes, Recessive; Humans; Infant, Newborn; Kidney Diseases; Kidney Glomerulus; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Spinocerebellar Degenerations; Ubiquinone

The bc1 complex is a central complex in the mitochondrial respiratory chain. It links the electrons transfer from ubiquinol (or coenzyme Q) to cytochrome c and proton translocation across the inner mitochondrial membrane. It is widely agreed that the "Q-cycle mechanism" proposed by Mitchell correctly describes the bc1 complex working. It is based on an unexpected separation of the two electrons coming from the coenzyme Q bound at the Q0 site of the bc1 complex. Using the stochastic approach of Gillespie and the known spatial structure of bc1 complexes with the kinetic parameters described by Moser and Dutton we demonstrated the natural emergence of the Q-cycle mechanism and the quasi absence of short-circuits in the functional dimer of bc1 complex without the necessity to invoke any additional mechanism. This approach gives a framework which is well adapted to the modelling of all oxido-reduction reactions of the respiratory chain complexes, normal or mutant.

Topics: Adenosine Triphosphate; Animals; Dimerization; Electron Transport; Electron Transport Complex III; Humans; Mitochondrial Diseases; Mitochondrial Membranes; Models, Biological; Models, Molecular; Oxidative Phosphorylation; Protein Conformation; Stochastic Processes; Ubiquinone

Mitochondrial disorders (MDs) are caused by impairment of the mitochondrial electron transport chain (ETC). The ETC is needed for oxidative phosphorylation, which provides the cell with the most efficient energy outcome in terms of ATP production. One of the pathogenic mechanisms of MDs is the accumulation of reactive oxygen species. Mitochondrial dysfunction and oxidative stress appear to also have a strong impact on the pathogenesis of neurodegenerative diseases and cancer. The treatment of MDs is still inadequate. Therapies that have been attempted include ETC cofactors, other metabolites secondarily decreased in MDs, antioxidants, and agents acting on lactic acidosis. However, the role of these dietary supplements in the treatment of the majority of MDs remains unclear. This article reviews the rationale for their use and their role in clinical practice in the context of MDs and other disorders involving mitochondrial dysfunction.

Topics: Acidosis, Lactic; Animals; Antioxidants; Carnitine; Creatine; Dietary Supplements; Electron Transport; Humans; Mitochondrial Diseases; Succinic Acid; Thioctic Acid; Ubiquinone; Vitamin B Complex; Vitamins

Coenzyme Q (CoQ) is an essential component of the respiratory chain but also participates in other mitochondrial functions such as regulation of the transition pore and uncoupling proteins. Furthermore, this compound is a specific substrate for enzymes of the fatty acids beta-oxidation pathway and pyrimidine nucleotide biosynthesis. Furthermore, CoQ is an antioxidant that acts in all cellular membranes and lipoproteins. A complex of at least ten nuclear (COQ) genes encoded proteins synthesizes CoQ but its regulation is unknown. Since 1989, a growing number of patients with multisystemic mitochondrial disorders and neuromuscular disorders showing deficiencies of CoQ have been identified. CoQ deficiency caused by mutation(s) in any of the COQ genes is designated primary deficiency. Other patients have displayed other genetic defects independent on the CoQ biosynthesis pathway, and are considered to have secondary deficiencies. This review updates the clinical and molecular aspects of both types of CoQ deficiencies and proposes new approaches to understanding their molecular bases.

Topics: Humans; Mitochondrial Diseases; Neuromuscular Diseases; Ubiquinone

Mitochondrial disease confirmation and establishment of a specific molecular diagnosis requires extensive clinical and laboratory evaluation. Dual genome origins of mitochondrial disease, multi-organ system manifestations, and an ever increasing spectrum of recognized phenotypes represent the main diagnostic challenges. To overcome these obstacles, compiling information from a variety of diagnostic laboratory modalities can often provide sufficient evidence to establish an etiology. These include blood and tissue histochemical and analyte measurements, neuroimaging, provocative testing, enzymatic assays of tissue samples and cultured cells, as well as DNA analysis. As interpretation of results from these multifaceted investigations can become quite complex, the Diagnostic Committee of the Mitochondrial Medicine Society developed this review to provide an overview of currently available and emerging methodologies for the diagnosis of primary mitochondrial disease, with a focus on disorders characterized by impairment of oxidative phosphorylation. The aim of this work is to facilitate the diagnosis of mitochondrial disease by geneticists, neurologists, and other metabolic specialists who face the challenge of evaluating patients of all ages with suspected mitochondrial disease.

Topics: Carnitine; Central Nervous System; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Radiography; Ubiquinone

Topics: alpha-Galactosidase; Arginine; Child; Coenzymes; Glucosylceramidase; Heredodegenerative Disorders, Nervous System; Humans; Isoenzymes; Lysosomal Storage Diseases; Mitochondrial Diseases; Molecular Diagnostic Techniques; Myotonic Dystrophy; Peripheral Nervous System Diseases; Peroxisomal Disorders; Trinucleotide Repeats; Ubiquinone; Vitamin E

Mevalonic aciduria (MVA) and phenylketonuria (PKU) are inborn errors of metabolism caused by deficiencies in the enzymes mevalonate kinase and phenylalanine 4-hydroxylase, respectively. Despite numerous studies the factors responsible for the pathogenicity of these disorders remain to be fully characterised. In common with MVA, a deficit in coenzyme Q10 (CoQ10) concentration has been implicated in the pathophysiology of PKU. In MVA the decrease in CoQ10 concentration may be attributed to a deficiency in mevalonate kinase, an enzyme common to both CoQ10 and cholesterol synthesis. However, although dietary sources of cholesterol cannot be excluded, the low/normal cholesterol levels in MVA patients suggests that some other factor may also be contributing to the decrease in CoQ10.The main factor associated with the low CoQ10 level of PKU patients is purported to be the elevated phenylalanine level. Phenylalanine has been shown to inhibit the activities of both 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase, enzymes common to both cholesterol and CoQ10 biosynthesis. Although evidence of a lowered plasma/serum CoQ10 level has been reported in MVA and PKU, few studies have assessed the intracellular CoQ10 concentration of patients. Plasma/serum CoQ10 is influenced by dietary intake as well as its lipoprotein content and therefore may be limited as a means of assessing intracellular CoQ10 concentration. Whether the pathogenesis of MVA and PKU are related to a loss of CoQ10 has yet to be established and further studies are required to assess the intracellular CoQ10 concentration of patients before this relationship can be confirmed or refuted.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Antioxidants; Coenzymes; Humans; Hydroxymethylglutaryl CoA Reductases; Metabolic Networks and Pathways; Mevalonic Acid; Mitochondrial Diseases; Models, Biological; Oxidative Stress; Phenylalanine; Phenylketonurias; Ubiquinone

Mitochondrial oxidative damage contributes to a range of degenerative diseases. Ubiquinones have been shown to protect mitochondria from oxidative damage, but only a small proportion of externally administered ubiquinone is taken up by mitochondria. Conjugation of the lipophilic triphenylphosphonium cation to a ubiquinone moiety has produced a compound, MitoQ, which accumulates selectively into mitochondria. MitoQ passes easily through all biological membranes and, because of its positive charge, is accumulated several hundred-fold within mitochondria driven by the mitochondrial membrane potential. MitoQ protects mitochondria against oxidative damage in vitro and following oral delivery, and may therefore form the basis for mitochondria-protective therapies.

Topics: Administration, Oral; Animals; Cations; Cell Membrane; Humans; Membrane Potential, Mitochondrial; Membrane Potentials; Mitochondria; Mitochondrial Diseases; Models, Biological; Models, Chemical; Organophosphorus Compounds; Oxygen; Quinones; Ubiquinone

The evidence supporting a treatment benefit for coenzyme Q10 (CoQ10) in primary mitochondrial disease (mitochondrial disease) whilst positive is limited. Mitochondrial disease in this context is defined as genetic disease causing an impairment in mitochondrial oxidative phosphorylation (OXPHOS). There are no treatment trials achieving the highest Level I evidence designation. Reasons for this include the relative rarity of mitochondrial disease, the heterogeneity of mitochondrial disease, the natural cofactor status and easy 'over the counter availability' of CoQ10 all of which make funding for the necessary large blinded clinical trials unlikely. At this time the best evidence for efficacy comes from controlled trials in common cardiovascular and neurodegenerative diseases with mitochondrial and OXPHOS dysfunction the etiology of which is most likely multifactorial with environmental factors playing on a background of genetic predisposition. There remain questions about dosing, bioavailability, tissue penetration and intracellular distribution of orally administered CoQ10, a compound which is endogenously produced within the mitochondria of all cells. In some mitochondrial diseases and other commoner disorders such as cardiac disease and Parkinson's disease low mitochondrial or tissue levels of CoQ10 have been demonstrated providing an obvious rationale for supplementation. This paper discusses the current state of the evidence supporting the use of CoQ10 in mitochondrial disease.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Coenzymes; Evidence-Based Medicine; Guinea Pigs; Humans; Mitochondria; Mitochondrial Diseases; Models, Biological; Oxidative Phosphorylation; Oxygen; Phosphorylation; Rats; Ubiquinone

Mitochondrial disorders encompass any medical specialty and affect patients at any age. Likewise, the spectrum of clinical and genetic signatures of these disorders is ample, making a precise diagnosis difficult. We will report some of the major clinical phenotypes observed in infancy, their underlining molecular features, and will propose an approach to reach a more complete diagnosis.

Topics: Brain; Coenzymes; DNA, Mitochondrial; Electron Transport Complex I; Humans; Infant; Leigh Disease; Mitochondrial Diseases; Mutation; Succinate-CoA Ligases; Ubiquinone

Coenzyme Q(10) (CoQ) deficiency is an autosomal recessive disorder presenting five phenotypes: a myopathic form, a severe infantile neurological syndrome associated with nephritic syndrome, an ataxic variant, Leigh syndrome and a pure myopathic form. The third is the most common phenotype related with CoQ deficiency and it will be the focus of this review. This new syndrome presents muscle CoQ deficiency associated with cerebellar ataxia and cerebellar atrophy as the main neurological signs. Biochemically, the hallmark of CoQ deficiency syndrome is a decreased CoQ concentration in muscle and/or fibroblasts. There is no molecular evidence of the enzyme or gene involved in primary CoQ deficiencies associated with cerebellar ataxia, although recently a family has been reported with mutations at COQ2 gene who present a distinct phenotype. Patients with primary CoQ deficiency may benefit from CoQ supplementation, although the clinical response to this therapy varies even among patients with similar phenotypes. Some present an excellent response to CoQ while others show only a partial improvement of some symptoms and signs. CoQ deficiency is the mitochondrial encephalomyopathy with the best clinical response to CoQ supplementation, highlighting the importance of an early identification of this disorder.

Topics: Alkyl and Aryl Transferases; Atrophy; Cerebellar Ataxia; Cerebellum; Coenzymes; Genetic Predisposition to Disease; Humans; Mitochondria; Mitochondrial Diseases; Ubiquinone

Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. Mitochondria produce large amounts of free radicals, and mitochondrial oxidative damage can contribute to a range of degenerative conditions including cardiovascular diseases (CVDs). Although the molecular mechanisms responsible for mitochondrion-mediated disease processes are not correctly understood, oxidative stress seems to play an important role. Consequently, the selective inhibition of mitochondrial oxidative damage is an obvious therapeutic strategy. This review considers the process of CVD from a mitochondrial perspective and provides a summary of the following areas: reactive oxygen species (ROS) production and its role in pathophysiological processes such as CVD, currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases, and recent developments in mitochondria-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane. These mitochondrion-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to antioxidant moieties such as ubiquinol. These compounds pass easily through biological membranes and, due to their positive charge, they accumulate several-hundred-fold within mitochondria. In this way they protect against mitochondrial oxidative damage and show potential as a future therapy for CVDs.

Topics: Antioxidants; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Humans; Membrane Potentials; Mitochondria; Mitochondrial Diseases; Nitric Oxide; Organophosphorus Compounds; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury; Risk Factors; Ubiquinone

Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration.. Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models.. The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'.

Topics: DNA, Mitochondrial; Genetic Predisposition to Disease; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Neurodegenerative Diseases; Oxidative Phosphorylation; Ubiquinone

Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear.. To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease.. We searched the Cochrane Neuromuscular Disease Group trials register (searched September 2003), the Cochrane Central Register of Controlled Trials, MEDLINE (January 1966 to October 3 2003), EMBASE (January 1980 to October 3 2003) and the European Neuromuscular Centre (ENMC) clinical trials register, and contacted experts in the field.. We included randomised controlled trials (including crossover studies) and quasi-randomised trials comparing pharmacological treatments, and non-pharmacological treatments (vitamins and food supplements), and physical training in individuals with mitochondrial disorders. The primary outcome measures included an improvement in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes.. Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention to treat data. We planned to use meta-analysis, but this did not prove necessary.. Six hundred and seventy-eight abstracts were reviewed, and six fulfilled the entry criteria. Two trials studied the effects of co-enzyme Q10 (ubiquinone), one reporting a subjective improvement and a significant increase in a global scale of muscle strength, but the other trial did not show any benefit. Two trials used creatine, with one reporting improved measures of muscle strength and post-exercise lactate, but the other reported no benefit. One trial of dichloroacetate showed an improvement in secondary outcome measures of mitochondrial metabolism, and one trial using dimethylglycine showed no significant effect.. There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches.

Topics: Creatine; Dichloroacetic Acid; Humans; Mitochondrial Diseases; Sarcosine; Ubiquinone

Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.

Topics: Animals; Female; Genotype; Humans; Male; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype; Ubiquinone

Topics: Antioxidants; Coenzymes; Diabetic Angiopathies; DNA Damage; DNA, Mitochondrial; Drug Design; Electron Transport; Humans; Insulin Resistance; Mitochondria; Mitochondrial Diseases; Mutation; Oxidative Stress; Signal Transduction; Superoxides; Thiamine; Transcription Factors; Ubiquinone

In this review we examine early and recent evidence for an aggregated organization of the mitochondrial respiratory chain. Blue Native Electrophoresis suggests that in several types of mitochondria Complexes I, III and IV are aggregated as fixed supramolecular units having stoichiometric proportions of each individual complex. Kinetic evidence by flux control analysis agrees with this view, however the presence of Complex IV in bovine mitochondria cannot be demonstrated, presumably due to high levels of free Complex. Since most Coenzyme Q appears to be largely free in the lipid bilayer of the inner membrane, binding of Coenzyme Q molecules to the Complex I-III aggregate is forced by its dissociation equilibrium; furthermore free Coenzyme Q is required for succinate-supported respiration and reverse electron transfer. The advantage of the supercomplex organization is in a more efficient electron transfer by channelling of the redox intermediates and in the requirement of a supramolecular structure for the correct assembly of the individual complexes. Preliminary evidence suggests that dilution of the membrane proteins with extra phospholipids and lipid peroxidation may disrupt the supercomplex organization. This finding has pathophysiological implications, in view of the role of oxidative stress in the pathogenesis of many diseases.

Topics: Animals; Electron Transport; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Humans; Kinetics; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Multienzyme Complexes; Phospholipids; Protein Structure, Quaternary; Ubiquinone

Topics: Amyotrophic Lateral Sclerosis; Child; Clinical Trials as Topic; Coenzymes; Friedreich Ataxia; Heart Arrest; Humans; Huntington Disease; Mitochondrial Diseases; Nervous System Diseases; Parkinson Disease; Ubiquinone

Topics: Antioxidants; Arginine; Child; Dichloroacetic Acid; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Mutation; Ubiquinone; Vitamins

Topics: Electron Transport; Humans; Mitochondria; Mitochondrial Diseases; Ubiquinone

There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Coenzymes; Humans; Mitochondria; Mitochondrial Diseases; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Ubiquinone

Nuclear genes encode hundreds of proteins involved in mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Nevertheless, the identification of nuclear genes responsible for OXPHOS-related disorders has proceeded at a much slower pace, compared with the discovery and characterization of mtDNA mutations. Reasons for such a gap include rarity of syndromes, genetic heterogeneity, and ignorance on this nuclear gene repertoire in humans. This scenario is changing rapidly, thanks to the discovery of several OXPHOS-related human genes, and to the identification in some of them of disease-associated mutations. In addition, new strategies - based on transcriptome and proteome analysis, and functional complementation assays - have been applied successfully to mitochondrial medicine.

Topics: Cell Nucleus; Humans; Mitochondrial Diseases; Oxidative Phosphorylation; Saccharomyces cerevisiae; Ubiquinone

We present here a review of the most recent and relevant contributions on the genetic, biochemical and clinical aspects of mitochondrial biogenesis and disease. The field of mitochondrial medicine is evolving fast. After more than 10 years of investigation into mitochondrial DNA defects, a new impulse is now due to progress in three main areas of research.. Some of the basic notions on mitochondrial genetics are being challenged by new data on fundamental biological functions such as mitochondrial DNA replication, transcription and the nuclear control of mitochondrial DNA variations, with important implications in the understanding of the molecular mechanisms of disease. The rapidly increasing identification of nuclear genes responsible for oxidative phosphorylation-related disorders, has greatly broadened the concept of mitochondrial disease.. The development of animal models and the use of multiple strategies are all accelerating our understanding of the pathogenesis in mitochondrial disorders, by integrating in-vivo, in-vitro and in-silico approaches. Finally, some interesting progress has recently been made on gene therapy, giving hope for the future treatment of these conditions.

Topics: Animals; Antioxidants; Coenzymes; Cytoprotection; DNA, Mitochondrial; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Oxidative Phosphorylation; Ubiquinone

The inherited disorders of muscle metabolism affect both substrate utilization and the final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Almost every step of these complex biochemical pathways can be affected by inborn errors, whose expression depends on peculiar tissue-specific or systemic gene expression. This review updates current knowledge in this broad field.. New inherited defects are still being discovered, such as the beta-enolase deficiency in glycogenosis type XIII and mutations in the gene encoding an esterase/lipase/thioesterase protein in Chanarin-Dorfman syndrome, a multisystem triglyceride storage disease.. Therapeutic approaches to the metabolic myopathies are still lagging behind, although remarkable observations have been made on the rare coenzyme Q10 deficiency syndrome. However, transgenic animal models may offer the opportunity both to investigate muscle pathogenesis and explore therapeutic targets. Finally, human myotoxicity may provide novel paradigms for naturally occurring muscle disorders.

Topics: Animals; Animals, Genetically Modified; Antioxidants; Coenzymes; Glycogen Storage Disease; Humans; Hypolipidemic Agents; Lipid Metabolism; Metabolism, Inborn Errors; Mitochondria, Muscle; Mitochondrial Diseases; Muscular Diseases; Mutation; Phosphopyruvate Hydratase; Ubiquinone

Topics: Coenzymes; Diagnosis, Differential; Humans; Lactic Acid; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Myoglobinuria; Prognosis; Syndrome; Ubiquinone

Topics: Carnitine; Coenzymes; Cytochrome c Group; Cytochromes c; Dichloroacetic Acid; Drug Combinations; Drug Therapy, Combination; Flavin Mononucleotide; Humans; Mitochondrial Diseases; Succinic Acid; Thiamine; Thiamine Pyrophosphate; Ubiquinone

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acyl-CoA Dehydrogenase, Long-Chain; Carnitine O-Palmitoyltransferase; Coenzymes; Cytochrome-c Oxidase Deficiency; Electron Transport Complex I; Fatty Acid Desaturases; Humans; Mitochondrial Diseases; Myoglobinuria; NADH, NADPH Oxidoreductases; Recurrence; Ubiquinone

Fibromyalgia (FM) is characterized by generalized pain and chronic fatigue of unknown etiology. To evaluate the role of oxidative stress in this disorder, we measured plasma levels of ubiquinone-10, ubiquinol-10, free cholesterol (FC), cholesterol esters (CE), and free fatty acids (FFA) in patients with juvenile FM (n=10) and in healthy control subjects (n=67). Levels of FC and CE were significantly increased in juvenile FM as compared with controls, suggesting the presence of hypercholesterolemia in this disease. However, plasma level of ubiquinol-10 was significantly decreased and the ratio of ubiquinone-10 to total coenzyme Q10 (%CoQ10) was significantly increased in juvenile FM relative to healthy controls, suggesting that FM is associated with coenzyme Q10 deficiency and increased oxidative stress. Moreover, plasma level of FFA was significantly higher and the content of polyunsaturated fatty acids (PUFA) in total FFA was significantly lower in FM than in controls, suggesting increased tissue oxidative damage in juvenile FM. Interestingly, the content of monoenoic acids, such as oleic and palmitoleic acids, was significantly increased in FM relative to controls, probably to compensate for the loss of PUFA. Next, we examined the effect of ubiquinol-10 supplementation (100 mg/day for 12 weeks) in FM patients. This resulted in an increase in coenzyme Q10 levels and a decrease in %CoQ10. No changes were observed in FFA levels or their composition. However, plasma levels of FC and CE significantly decreased and the ratio of FC to CE also significantly decreased, suggesting that ubiquinol-10 supplementation improved cholesterol metabolism. Ubiquinol-10 supplementation also improved chronic fatigue scores as measured by the Chalder Fatigue Scale.

Topics: Adolescent; Antioxidants; Ataxia; Case-Control Studies; Child; Cholesterol; Dietary Supplements; Double-Blind Method; Fatigue; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Fibromyalgia; Humans; Hypercholesterolemia; Male; Mitochondrial Diseases; Muscle Weakness; Oleic Acid; Oxidative Stress; Pain Measurement; Ubiquinone

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Topics: Adolescent; Adult; Benzoquinones; Brain; Cells, Cultured; Child; Child, Preschool; Female; Fibroblasts; Gene Expression Regulation; Genetic Diseases, Inborn; Humans; Male; Mitochondrial Diseases; Oxidative Stress; Oximes; Tomography, Emission-Computed, Single-Photon; Ubiquinone

We report the design and implementation of the first phase 3 trial of CoenzymeQ₁₀ (CoQ₁₀) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ₁₀ by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation--and ultimate approval--of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.

Topics: Biomedical Research; Humans; Mitochondrial Diseases; Research Design; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ(10) levels have been detected in patients with Fibromyalgia (FM). The purpose of the present work was to assess the effect of CoQ(10) on symptoms of five patients with FM. Patients were evaluated clinically with Visual Analogical Scale of pain (VAS), and Fibromyalgia Impact Questionnaire (FIQ). Patients with CoQ(10) deficiency showed a statistically significant reduction on symptoms after CoQ(10) treatment during 9 months (300 mg/day). Determination of deficiency and consequent supplementation in FM may result in clinical improvement. Further analysis involving more scientifically rigorous methodology will be required to confirm this observation.

Topics: Adult; Aged; Antioxidants; Female; Fibromyalgia; Humans; Lipid Peroxidation; Male; Middle Aged; Mitochondrial Diseases; Oxidative Stress; Pain Measurement; Patients; Plasma; Reactive Oxygen Species; Ubiquinone; Young Adult

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.

Topics: Absorptiometry, Photon; Activities of Daily Living; Adult; Anaerobic Threshold; Antioxidants; Body Composition; Brain Chemistry; Choline; Cross-Over Studies; Double-Blind Method; Exercise Test; Female; Forearm; Hemodynamics; Humans; Isometric Contraction; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondrial Diseases; Muscle Fatigue; Oxidative Stress; Oxygen Consumption; Quality of Life; Spectroscopy, Near-Infrared; Ubiquinone

Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Analysis of Variance; Antioxidants; Body Composition; Child; Coenzymes; Creatine; Creatinine; Cross-Over Studies; Deoxyguanosine; Dinoprost; Double-Blind Method; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Thioctic Acid; Ubiquinone

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Topics: Adenosine Triphosphate; Adolescent; Adult; Antioxidants; Child; Coenzymes; Dose-Response Relationship, Drug; Female; Humans; Lymphocytes; Male; Middle Aged; Mitochondrial Diseases; Ubiquinone

Topics: Chromatography, High Pressure Liquid; Coenzymes; Humans; Malignant Hyperthermia; Mitochondrial Diseases; Muscle, Skeletal; Spectrophotometry, Ultraviolet; Ubiquinone

Coenzyme Q10 (CoQ10) is frequently administered in mitochondrial diseases. Mitochondrial dysfunction and CoQ10 treatment was also proposed in neurodegenerative disorders as amyotrophic lateral sclerosis and Parkinsons disease.. Seventeen patients with mitochondrial CPEO were treated with CoQ10 (dosage: 0.60 1.80 mg/kg body wt) in an open trial. Serum levels of CoQ10 were monitored before and after 6-9 and 12-15 months of CoQ10 therapy. CoQ10 concentration in muscle was measured in all patients before treatment.. Prior to treatment CoQ10 concentration in muscle was normal in all patients. Eight patients completed the study after 12-15 months. Prior to treatment there was no correlation between CoQ10 in muscle and serum. There was no inverse correlation of serum lactate with CoQ10 in muscle before and in serum before and during therapy. CoQ10 serum level and body weight related CoQ10 dosage correlated significantly after 6-9 months but not after 12-15 months (p = 0.043 and n. s., respectively). During continued administration of CoQ10 the CoQ10 serum level was increased 2.76 +/- 1.00-fold after 6-9 months (range: 1.04-3.80). but returned to 1.70 +/- 0.98-fold after 12-15 months (range: 0.91-3.83). Serum lactate did not significantly change during treatment. There was no effect of CoQ10 treatment on signs and symptoms.. The only transient increase of CoQ10 in serum has to be considered in any low dose long-term treatment with CoQ10.

Topics: Adolescent; Adult; Aged; Antioxidants; Coenzymes; Female; Humans; Lactic Acid; Male; Middle Aged; Mitochondrial Diseases; Muscle, Skeletal; Ophthalmoplegia; Physical Exertion; Rest; Ubiquinone

Coenzyme Q10 (CoQ10) serves as an electron carrier within the mitochondrial respiratory chain (MRC), where it is integrally involved in oxidative phosphorylation and consequently ATP production. It has recently been suggested that phenylketonuria (PKU) patients may be susceptible to a CoQ10 deficiency as a consequence of their phenylalanine-restricted diet, which avoids foods rich in CoQ10 and its precursors. Furthermore, the high phenylalanine level in PKU patients not on dietary restriction may also result in impaired endogenous CoQ10 production, as previous studies have suggested an inhibitory effect of phenylalanine on HMG-CoA reductase, the rate-controlling enzyme in CoQ10 biosynthesis. We investigated the effect of both dietary restriction and elevated plasma phenylalanine concentration on blood mononuclear cell CoQ10 concentration and the activity of MRC complex II + III (succinate:cytochrome-c reductase; an enzyme that relies on endogenous CoQ10) in a PKU patient population. The concentrations of CoQ10 and MRC complex II + III activity were not found to be significantly different between the PKU patients on dietary restriction, PKU patients off dietary restriction and the control group, although plasma phenylalanine levels were markedly different. The results from this investigation suggest that dietary restriction and the elevated plasma phenylalanine levels of PKU patients do not effect mononuclear cell CoQ10 concentration and consequently the activity of complex II + III of the MRC.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Citrate (si)-Synthase; Coenzymes; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Male; Middle Aged; Mitochondrial Diseases; Monocytes; Phenylalanine; Phenylketonurias; Succinate Cytochrome c Oxidoreductase; Ubiquinone

Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Topics: Ataxia; Child, Preschool; Humans; Male; Mitochondrial Diseases; Mutation; Ubiquinone

Isolated complex III defect is a relatively rare cause of mitochondrial disorder. New genes involved were identified in the last two decades, with only a few cases described for each deficiency. UQCRC2, which encodes ubiquinol-cytochrome c reductase core protein 2, is one of the eleven structural subunits of complex III. We report seven French patients with UQCRC2 deficiency to complete the phenotype reported so far. We highlight the similarities with neoglucogenesis defect during decompensations - hypoglycaemias, liver failure and lactic acidosis - and point out the rapid improvement with glucose fluid infusion, which is a remarkable feature for a mitochondrial disorder. Finally, we discuss the relevance of coenzyme Q10 supplementation in this defect.

Topics: Acidosis, Lactic; Electron Transport Complex III; Humans; Mitochondrial Diseases; Phenotype; Ubiquinone

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary CoQ10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. High-performance liquid chromatography assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. Induced pluripotent stem cell-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with distal hereditary motor neuropathy. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease.

Topics: Humans; Mitochondria; Mitochondrial Diseases; Motor Neurons; Mutation; Ubiquinone

Primary coenzyme Q10 (CoQ

Topics: Humans; Infant, Newborn; Mitochondria; Mitochondrial Diseases; Ubiquinone

Topics: Humans; Mitochondrial Diseases; Motor Neurons; Ubiquinone

Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor composed of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for haem biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p failed to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enabled robust IPP uptake and incorporation into the CoQ biosynthetic pathway. HEM25 orthologues from diverse fungi, but not from metazoans, were able to rescue hem25∆ CoQ deficiency. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in fungi.

Topics: Ataxia; Humans; Mitochondria; Mitochondrial Diseases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Coenzyme Q10 deficiency can be due to mutations in Coenzyme Q10-biosynthesis genes (primary) or genes unrelated to biosynthesis (secondary). Primary Coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is an autosomal recessive disorder caused by mutations in the ADCK3 gene. This disorder is characterized by several clinical manifestations such as severe infantile multisystemic illness, encephalomyopathy, isolated myopathy, cerebellar ataxia, or nephrotic syndrome.. In this study, whole-exome sequencing was performed in order to identify disease-causing variants in an affected girl with developmental regression and Epilepsia Partialis Continua (EPC). Next, Sanger sequencing method was used to confirm the identified variant in the patient and segregation analysis in her parents.. The proband is an affected 11-year-old girl with persistent seizures, EPC, and developmental regression including motor, cognition, and speech. Seizures were not controlled with various anticonvulsant drugs despite adequate dosing. Progressive cerebellar atrophy, stroke-like cortical involvement, multifocal hyperintense bright objects, and restriction in diffusion-weighted imaging (DWI) were seen in the brain magnetic resonance imaging (MRI).. A novel homozygous missense variant [NM_020247.5: c.814G>T; (p.Gly272Cys)] was identified within the ADCK3 gene, which is the first mutation in this gene in the Iranian population. Bioinformatics analysis showed this variant is damaging. Based on our patient, clinicians should consider genetic testing earlier to instant diagnosis and satisfactory treatment based on exact etiology to prevent further neurologic sequelae.

Topics: Ataxia; Child; Epilepsia Partialis Continua; Female; Humans; Iran; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Brown adipose tissue (BAT) mitochondria generate heat via uncoupled respiration due to excessive proton leak through uncoupling proteins (UCPs). We previously found hyperthermia in a newborn mouse model of fragile X syndrome and excessive leak in Fmr1 KO forebrain mitochondria caused by CoQ deficiency. The inefficient thermogenic nature of Fmr1 mutant forebrain mitochondria was reminiscent of BAT metabolic features. Thus, we aimed to characterize BAT mitochondrial function in these hyperthermic mice using a top-down approach. Although there was no change in steady-state levels of UCP1 expression between strains, BAT weighed significantly less in Fmr1 mutants compared with controls. Fmr1 KO BAT mitochondria demonstrated impaired substrate oxidation, lower mitochondrial membrane potentials and rates of respiration, and CoQ deficiency. The CoQ analog decylubiquinone normalized CoQ-dependent electron flux and unmasked excessive proton leak. Unlike mutant forebrain, where such deficiency resulted in pathological proton leak, CoQ deficiency within BAT mitochondria resulted largely in abnormal substrate oxidation. This suggests that CoQ is important in BAT for uncoupled respiration to produce heat during development. Although our data provide further evidence of a link between fragile X mental retardation protein (FMRP) and CoQ biosynthesis, the results highlight the importance of CoQ in developing tissues and suggest tissue-specific differences from CoQ deficiency. Because BAT mitochondria are primarily responsible for regulating core body temperature, the defects we describe in Fmr1 KOs could manifest as an adaptive downregulated response to hyperthermia or could result from FMRP deficiency directly.

Topics: Adipose Tissue, Brown; Animals; Ataxia; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Protons; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency, a recessive disorder associated with various defects of CoQ10 biosynthesis and widely varying clinical presentation, is customarily managed by oral Q10 supplementation but the benefit is debated.. To address this question, we mapped individual responses in two patients with COQ8A-related ataxia following coenzyme Q10 supplementation using noninvasive imaging. Metabolic. Post-treatment change in energy metabolite levels differed in the two patients, with higher energy levels and improved dysarthria and leg coordination in one, and decreased energy levels without clinical benefit in the other.. Our results suggest that the cerebellar bioenergetic state may predict treatment response in COQ8A-related ataxia and highlight the potential of pathophysiology-orientated neuroimaging evidence to inform treatment decisions.

Topics: Ataxia; Cerebellar Ataxia; Energy Metabolism; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Primary Coenzyme Q10 (CoQ

Topics: Ataxia; Dietary Supplements; Humans; Kidney; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Proteinuria; Steroids; Ubiquinone

We report a 19-month-old patient with cardiomyopathy as the first presenting feature of primary COQ10 deficiency-6. This case expands the phenotypic spectrum of this disorder. Furthermore, it shows that genetic testing for primary COQ10 deficiency should be considered in patients with pediatric-onset cardiomyopathy as it can guide treatment options.

Topics: Ataxia; Cardiomyopathies; Humans; Infant; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone

Coenzyme Q10 (CoQ10) plays an essential electron carrier role in the mitochondrial electron transfer chain (ETC) as well as being a potent antioxidant and influencing inflammatory mediators. In view of these functions, the reason why certain individuals may be more susceptible to the severe disease or long-term complications (long COVID) of COVID-19 infection may be associated with an underlying deficit in cellular CoQ10 status. Thus, our group has outlined an analytical method for the determination of cellular CoQ10 status using HPLC linked UV detection at 275 nm. This method has been utilized in patient tissue samples to investigate evidence of a CoQ10 deficiency and thus may have potential in determining the possible susceptibility of individuals to severe disease associated with COVID-19 infection or to long COVID.

Topics: COVID-19; Humans; Mitochondrial Diseases; Post-Acute COVID-19 Syndrome; Ubiquinone

COQ4 codes for a mitochondrial protein required for coenzyme Q. In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.. Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ. We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: Ataxia; Cerebellar Ataxia; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Spasticity; Muscle Weakness; Mutation; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency refers to a group of mitochondrial cytopathies caused by genetic defects in CoQ10 biosynthesis. Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder attributable to biallelic

Topics: Ataxia; Deafness; Hearing Loss, Sensorineural; Humans; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Steroids; Ubiquinone

Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.

Topics: Ataxia; Humans; Manganese; Mitochondrial Diseases; Mixed Function Oxygenases; Muscle Weakness; Ubiquinone

Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.

Topics: Animals; Genetic Testing; Mice; Mitochondrial Diseases; Oxidation-Reduction; Phosphatidylethanolamine N-Methyltransferase; Phospholipids; Ubiquinone

To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined deficiencies of the mitochondrial respiratory chain complexes.. Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients.. Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coenzyme Q10 in muscle, irrespective of genetic cause.. Children with combined enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.

Topics: Adolescent; Adult; Child; Child, Preschool; DNA Mutational Analysis; DNA, Mitochondrial; Exome Sequencing; Humans; Infant; Infant, Newborn; Metabolic Diseases; Mitochondrial Diseases; Mutation; Ubiquinone; Young Adult

Coenzyme Q

Topics: Alkyl and Aryl Transferases; Ataxia; Cell Line, Tumor; Cholesterol; Energy Metabolism; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nitrobenzoates; Protein Stability; Ubiquinone

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency).

Topics: Adolescent; Alkyl and Aryl Transferases; Ataxia; Child; Consanguinity; Female; Hearing Loss, Sensorineural; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; Optic Atrophies, Hereditary; Ubiquinone

Coenzyme Q10 (CoQ10) is involved in the biosynthesis of adenosine triphosphate (ATP), and is most abundant in the mitochondrial membrane. The primary CoQ10 deficiency caused by. Clinical and pathological data and peripheral blood samples of 2 siblings with steroid-resistant nephrotic syndrome (SRNS) and their family members of a Chinese pedigree were collected. DNA was extracted and subjected to next-generation sequencing of target genes of hereditary nephropathy.. Compound heterozygous mutations of. The 2 cases harboring

Topics: Alkyl and Aryl Transferases; Child, Preschool; China; Female; Glomerulosclerosis, Focal Segmental; Humans; Infant; Male; Mitochondrial Diseases; Mutation; Nephrotic Syndrome; Pedigree; Proteinuria; Siblings; Ubiquinone

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.

Topics: Alkyl and Aryl Transferases; Animals; Ataxia; Drug Delivery Systems; HEK293 Cells; Humans; Indenes; Kidney Diseases; Lipid Peroxidation; MAP Kinase Signaling System; Mice; Mitochondrial Diseases; Muscle Weakness; Podocytes; Proto-Oncogene Proteins B-raf; Pyrazoles; RNA-Seq; Ubiquinone

Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Tissue Distribution; Ubiquinone

Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease.. Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases.. Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31 ± 0.03 µM vs 0.70 ± 0.06 µM, p < 0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1 ± 1.3 µM vs 29.9 ± 2.5 µM, p < 0.001, respectively), but no correlation was observed with CoQ10 levels.. The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.

Topics: Ataxia; Case-Control Studies; Female; Hemochromatosis; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Topics: Animals; Ataxia; Fibroblasts; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Muscles; Neurodevelopmental Disorders; Ubiquinone; Zebrafish

Topics: Electron Transport; Homeostasis; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Ubiquinone

Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 μM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.

Topics: Animals; Ataxia; Cell Line; Cell Survival; Heart Failure; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Fibers, Skeletal; Muscle Weakness; Muscular Diseases; Nanocomposites; Oxygen Consumption; Simvastatin; Ubiquinone

Intrahepatic cholestasis of pregnancy (ICP) is considered a high-risk condition because it may have serious consequences for the fetus health. ICP is characterized by the accumulation of bile acids in maternal serum which contribute to an imbalance between the production of reactive oxygen species and the antioxidant defenses increasing the oxidative stress experienced by the fetus. Previously, it was reported a significant decrease in plasma coenzyme Q10 (CoQ10) in women with ICP. CoQ10 is a redox substance integrated in the mitochondrial respiratory chain and is recognized as a potent antioxidant playing an intrinsic role against oxidative damage. The objective of the present study was to investigate the levels of CoQ10 in umbilical cord blood during normal pregnancy and in those complicated with ICP, all of them compared to the maternal ones.. CoQ10 levels and bile acid levels in maternal and umbilical cord blood levels during normal pregnancies (n=23) and in those complicated with ICP (n=13), were investigated.. A significant decrease in neonate CoQ10 levels corrected by cholesterol (0.105±0.010 vs. 0.069±0.011, P<0.05, normal pregnancy vs. ICP, respectively), together with an increase of total serum bile acids (2.10±0.02 vs. 7.60±2.30, P<0.05, normal pregnancy vs. ICP, respectively) was observed.. A fetus from an ICP mother is exposed to a greater risk derived from oxidative damage. The recognition of CoQ10 deficiency is important since it could be the starting point for a new and safe intervention strategy which can establish CoQ10 as a promising candidate to prevent the risk of oxidative stress.

Topics: Adult; Ataxia; Bile Acids and Salts; Biomarkers; Birth Weight; Cholestasis, Intrahepatic; Cholesterol; Cholic Acid; Cross-Sectional Studies; Female; Fetal Blood; Fetus; Gestational Age; Humans; Infant, Newborn; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Oxidative Stress; Pregnancy; Pregnancy Complications; Prospective Studies; Reactive Oxygen Species; Ubiquinone; Young Adult

Coenzyme Q

Topics: Ataxia; Biological Products; High-Throughput Screening Assays; Humans; Mitochondria; Mitochondrial Diseases; Models, Genetic; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Ubiquinone

Background Coenzyme Q10 (CoQ10) serves as a shuttle for electrons from complexes I and II to complex III in the respiratory chain, and has important functions within the mitochondria. Primary CoQ10 deficiency is a mitochondrial disorder which has devastating effects, and which may be partially treated with exogenous CoQ10 supplementation. Case presentation A 9-month-old girl patient was referred to our clinic due to growth retardation, microcephaly and seizures. She was the third child of consanguineous parents (first-degree cousins) of Pakistani origin, born at 38 weeks gestation, weighing 2000 g after an uncomplicated pregnancy, and was hospitalized for 3 days due to respiratory distress. She had sustained clonic seizures when she was 4 months old. Physical examination showed microcephaly, truncal hypotonia and dysmorphic features. Metabolic tests were inconclusive. Abdominal ultrasonography revealed cystic appearance of the kidneys. Non-compaction of the left ventricle was detected in echocardiography. Cranial magnetic resonance imaging (MRI) showed hypoplasia of the cerebellar vermis and brain stem, corpus callosum agenesis, and cortical atrophy. A panel testing of 450 genes involved in inborn errors of metabolism (IEM) was performed that showed a novel frameshift c.384delG (Gly129Valfs*17) homozygous mutation in COQ9. A treatment of 5 mg/kg/day exogenous CoQ10 was started when she was 10 months old, and the dosage was increased to 50 mg/kg/day after the exact diagnosis. No objective neurological improvement could be observed after the adjustment of the drug dosage. Conclusions We report a case of CoQ10 deficiency due to a novel COQ9 gene mutation that adds clinical data from a newly diagnosed patient. Our case also outlines the importance of genetic panels used for specific diseases including IEM.

Topics: Ataxia; Female; Humans; Infant; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Prognosis; Rare Diseases; Ubiquinone

Coenzyme Q

Topics: Ataxia; Cell Line, Tumor; Chromatography, High Pressure Liquid; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Neurons; Ubiquinone; Ultraviolet Rays

Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.

Topics: Animals; GTP-Binding Proteins; Humans; Lipids; Microfilament Proteins; Mitochondrial Diseases; N-Terminal Acetyltransferase B; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone; Vesicular Transport Proteins

Primary coenzyme Q10 deficiency refers to a group of diseases characterised by reduced levels of coenzyme Q10 in related tissues or cultured cells associated with the 9 genes involved in the biosynthesis of coenzyme Q10. A biallelic pathogenic variant of COQ8A gene causes the occurrence of the primary coenzyme Q10 deficiency type 4. The objective of this study was to investigate the genetic cause of muscle weakness in a proband who had a negative DMD gene test for Becker muscular dystrophy.. The DNA of the proband was sequenced using whole exome sequencing. With the help of the Human Phenotype Ontology (HPO), the range of related candidate pathogenic genes has been reduced to a certain extent based on "muscle weakness" (HP:0001324). In addition, family linkage analysis, phenotypic-genotype check and protein structure modeling were used to explore the genetic cause of the proband.. The compound heterozygous variant c.836A > C (p.Gln279Pro) and c.1228C > T (p.Arg410Ter) in the COQ8A gene was identified in the proband. According to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, the novel variant c.836A > C could be classified as "likely pathogenic" for the proband.. The p.Gln279Pro was detected in the KxGQ motif and the QKE triplet of the COQ8A protein, whose structures were crucial for the structure and function of the COQ8A protein associated with the biosynthesis of coenzyme Q10 and the proband's clinical symptoms were relatively milder than those previously reported.

Topics: Ataxia; Child; Exome Sequencing; Humans; Male; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation, Missense; Pedigree; Ubiquinone

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an important antioxidant present in all cellular membranes. CoQ deficiencies are frequent in aging and in age-related diseases, and current treatments are limited to CoQ supplementation. Strategies that rely on CoQ supplementation suffer from poor uptake and trafficking of this very hydrophobic molecule. In a previous study, the dietary flavonol kaempferol was reported to serve as a CoQ ring precursor and to increase the CoQ content in kidney cells, but neither the part of the molecule entering CoQ biosynthesis nor the mechanism were described. In this study, kaempferol labeled specifically in the B-ring was isolated from

Topics: Animals; Antioxidants; Ataxia; Epithelial Cells; Flavonols; Humans; Kaempferols; Kidney; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Muscle Weakness; Mutation; Ubiquinone

Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adult; Age of Onset; Ataxia; Child; Electron-Transferring Flavoproteins; Energy Metabolism; Humans; Iron-Sulfur Proteins; Male; Mitochondria; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Oxidoreductases Acting on CH-NH Group Donors; Ubiquinone; Young Adult

Coenzyme Q

Topics: Administration, Intravenous; Animals; Caspofungin; Fungicides, Industrial; Humans; Mice; Mitochondrial Diseases; Ubiquinone

Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.

Topics: Animals; Ataxia; Carbon; Electron Transport; Electron Transport Complex I; Fibroblasts; Glutathione; Humans; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidoreductases Acting on Sulfur Group Donors; Skin; Sulfides; Transcriptome; Ubiquinone; Vitamins

Topics: Ataxia; Fibroblasts; Humans; Infant; Male; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Ubiquinone

Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described.. Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings.. We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement.. We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Pedigree; Retrospective Studies; Ubiquinone

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

Topics: Ataxia; Child; Female; Homozygote; Humans; Kidney; Kidney Failure, Chronic; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Phenotype; Siblings; Ubiquinone

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.

Topics: Acidosis; Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases; Adrenergic beta-Antagonists; Amino Acid Metabolism, Inborn Errors; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Carvedilol; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Mitochondrial Diseases; Muscle Weakness; Prognosis; Pyruvates; Ubiquinone; Vitamins

Leigh syndrome is one of the most common childhood-onset neurometabolic disorders resulting from a primary oxidative phosphorylation dysfunction and affecting mostly brain tissues. Ndufs4

Topics: Adenosine Triphosphate; Animals; Electron Transport Complex I; Flavoproteins; Glycolysis; Leigh Disease; Male; Metabolomics; Mice; Mice, Knockout; Mitochondrial Diseases; Models, Animal; Muscle, Skeletal; Oxidation-Reduction; Oxidative Phosphorylation; Ubiquinone

COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.

Topics: Asian People; Ataxia; Child, Preschool; Computer Simulation; Female; Fibroblasts; Genetic Testing; Heterozygote; Homozygote; Humans; Infant; Leigh Disease; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Phenotype; Ubiquinone

Topics: Administration, Oral; Child, Preschool; Citrulline; DNA, Mitochondrial; Humans; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Mutation; Optic Atrophy, Hereditary, Leber; Tomography, Optical Coherence; Ubiquinone; Visual Acuity

Topics: Adult; Cerebellar Ataxia; Fibroblasts; Humans; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle, Skeletal; Mutation; Ubiquinone

The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown.. We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9. Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9. These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).

Topics: Animals; Autophagy; Cell Respiration; Disease Models, Animal; Gene Expression Profiling; Humans; Metabolomics; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Phenotype; Sirolimus; Treatment Outcome; Ubiquinone

Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies.. Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured.. EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE).. These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Topics: Arachidonate 15-Lipoxygenase; Carbolines; Cell Line; Epilepsy; Ferroptosis; Humans; Hydroxyeicosatetraenoic Acids; Mitochondrial Diseases; Phospholipid Hydroperoxide Glutathione Peroxidase; Ubiquinone

Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient's cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.

Topics: Ataxia; Cerebellar Ataxia; Child, Preschool; Female; Fibroblasts; Humans; Infant; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Ubiquinone

Coenzyme Q

Topics: Animals; Ataxia; Drosophila melanogaster; Electron Transport; HeLa Cells; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone; Vitamin K 2

Coenzyme Q (CoQ or ubiquinone) serves as an essential redox-active lipid in respiratory electron and proton transport during cellular energy metabolism. CoQ also functions as a membrane-localized antioxidant protecting cells against lipid peroxidation. CoQ deficiency is associated with multiple human diseases; CoQ

Topics: Antioxidants; Ataxia; Humans; Lipid Peroxidation; Mass Spectrometry; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidative Stress; Phosphoproteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases.. Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations.. Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.

Topics: Ataxia; Exome Sequencing; Female; Genetic Variation; Humans; Infant; Infant, Newborn; Male; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone

A 7-month-old male infant was admitted because he was suffering from nephrotic syndrome, along with encephalomyopathy, hypertrophic cardiomyopathy, clinically suspected deafness and retinitis pigmentosa, and an elevated serum lactate level.. Coenzyme Q. The results of genetic tests, available postmortem, explored two hitherto undescribed mutations in the PDSS2 gene. Both were located within the polyprenyl synthetase domain. Clinical exome sequencing revealed a heterozygous missense mutation in exon 3, and our in-house joint-analysis algorithm detected a heterozygous large 2923-bp deletion that affected the 5 prime end of exon 8. Other causative defects in the CoQ. Until now, the clinical features and the mutational status of 6 patients with a PDSS2 gene defect have been reported in the English literature. Here, we describe for the first time detailed kidney morphology features in a patient with nephrotic syndrome carrying mutations in the PDSS2 gene.

Topics: Alkyl and Aryl Transferases; Ataxia; Autopsy; Fatal Outcome; Genetic Testing; Humans; Infant; Kidney; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Sclerosis; Ubiquinone

Primary disorders of the human coenzyme Q

Topics: Animals; Apoptosis; Ataxia; Biosynthetic Pathways; Cytochrome P-450 Enzyme System; Disease Models, Animal; Humans; Hydroxybenzoates; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Pyrimidines; Solubility; Treatment Outcome; Ubiquinone; Vitamins

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Ataxia; Humans; Insulin Resistance; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Muscles; Oxidants; Sensitivity and Specificity; Ubiquinone

Coenzyme Q. Muscle samples were homogenized whereby 600 ×g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ. Central 95% reference intervals (RI) were established for CoQ. In this retrospective study, we report a central 95% reference interval for 600 ×g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ

Topics: Adult; Ataxia; Cells, Cultured; Electron Transport; Energy Metabolism; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Retrospective Studies; Ubiquinone

Primary CoQ

Topics: Acidosis, Lactic; Ataxia; Autopsy; Exome Sequencing; Female; Humans; Infant, Newborn; Leigh Disease; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Pregnancy; Siblings; Ubiquinone

Mitochondrial diseases are a group of devastating disorders for which there is no transformative cure. The majority of therapies for mitochondrial disease-approved, previously tested, or currently in development-are small molecules. The implementation of better cell-based models of mitochondrial disease can accelerate and improve the accuracy of small molecule drug discovery. The objective of this study is to evaluate the use of patient-derived lymphoblastoid cell lines for small molecule research in mitochondrial disease.. Five lymphoblastoid cell lines derived from mitochondrial disease patients harboring point mutations in mtND1, mtND4, or mtATP6 were characterized in two high throughput assays assessing mitochondrial function. In a pilot "clinical trial in a dish" experiment, the efficacy of idebenone-an approved therapy for mitochondrial disease-on the lymphoblastoid cell lines was tested. Idebenone increased the basal respiration of all lymphoblastoid cell lines except those harboring the 8993T>G point mutation in mtATP6. Our results posit lymphoblastoid cell lines as a strong model for mitochondrial disease research with small molecules and have implications for the clinical efficacy of idebenone.

Topics: Adult; Cell Line; Child; Child, Preschool; DNA, Mitochondrial; Drug Discovery; Female; Humans; Lymphocytes; Male; Mitochondrial Diseases; Oxygen Consumption; Point Mutation; Small Molecule Libraries; Ubiquinone; Young Adult

Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q. We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ. COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ

Topics: Alkyl and Aryl Transferases; Ataxia; Biopsy; Child; Child, Preschool; Genetic Testing; Humans; Kidney; Kidney Transplantation; Male; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Treatment Outcome; Ubiquinone

Idebenone is a hydrophilic short-chain coenzyme (Co) Q analogue, which has been used as a potential bypass of defective complex I in both Leber Hereditary Optic Neuropathy and OPA1-dependent Dominant Optic Atrophy. Based on its potential antioxidant effects, it has also been tested in degenerative disorders such as Friedreich's ataxia, Huntington's and Alzheimer's diseases. Idebenone is rapidly modified but the biological effects of its metabolites have been characterized only partially. Here we have studied the effects of quinones generated during in vivo metabolism of idebenone with specific emphasis on 6-(9-carboxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS10). QS10 partially restored respiration in cells deficient of complex I or of CoQ without inducing the mitochondrial permeability transition, a detrimental effect of idebenone that may offset its potential benefits [Giorgio et al. (2012) Biochim. Biophys. Acta 1817: 363-369]. Remarkably, respiration was largely rotenone-insensitive in complex I deficient cells and rotenone-sensitive in CoQ deficient cells. These findings indicate that, like idebenone, QS10 can provide a bypass to defective complex I; and that, unlike idebenone, QS10 can partially replace endogenous CoQ. In zebrafish (Danio rerio) treated with rotenone, QS10 was more effective than idebenone in allowing partial recovery of respiration (to 40% and 20% of the basal respiration of untreated embryos, respectively) and allowing zebrafish survival (80% surviving embryos at 60 h post-fertilization, a time point at which all rotenone-treated embryos otherwise died). We conclude that QS10 is potentially more active than idebenone in the treatment of diseases caused by complex I defects, and that it could also be used in CoQ deficiencies of genetic and acquired origin.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Ataxia; Cell Respiration; Cells, Cultured; Electron Transport; Electron Transport Complex I; Embryo, Nonmammalian; Mice; Mitochondria, Liver; Mitochondrial Diseases; Muscle Weakness; Ubiquinone; Zebrafish

Mitochondrial diseases are a group of rare multisystem disorders characterized by genetic heterogeneity and pleomorphic clinical manifestations. The clinical burden may be heavy for patients and their caregivers. There are no therapies of proven efficacy until now and a multidisciplinary supportive care is therefore necessary. Since the common pathogenic mechanism is the insufficient energy production by defective mitochondria, nutrition may play a crucial role. However, no guidelines are still available. The article reports the current evidence, highlighting nutrition both as support and as therapy. The estimate of nutritional status, energy needs and nutritional behaviors are firstly discussed. Then, we go in-depth on the scientific rationale and the clinical evidence of the use of anti-oxidants and enzyme-cofactors in the clinical practice. In particular, we analyze the role of Coenzyme Q10, Creatine monohydrate, α-lipoic acid, riboflavin, arginine and citrulline, folinic acid, carnitine, vitamin C, K, and E. Every attempt at nutritional intervention should be made knowing patient's disease and focusing on his/her energy and nutrients' requirements. For this reason, clinicians expert in mitochondrial medicine and clinical nutritionists should work together to ameliorate care in these fragile patients.

Topics: Arginine; Deglutition Disorders; Diet, High-Fat; Energy Metabolism; Humans; Mitochondria; Mitochondrial Diseases; Nutritional Support; Thioctic Acid; Ubiquinone

Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q

Topics: Alkyl and Aryl Transferases; Animals; Antioxidants; Ataxia; Disease Models, Animal; HeLa Cells; Humans; Hydrogen Sulfide; Kidney; Metabolic Networks and Pathways; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidation-Reduction; Oxidative Stress; Oxidoreductases Acting on Sulfur Group Donors; Reactive Oxygen Species; Ubiquinone

Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q

Topics: Ataxia; Cells, Cultured; Cholesterol; Fibroblasts; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Mitophagy; Muscle Weakness; Reactive Oxygen Species; Receptors, LDL; Ubiquinone

COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes.. We report four new patients from two families with the c.437G→A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment.. Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy.. In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.

Topics: Adaptor Proteins, Vesicular Transport; Ataxia; Cohort Studies; Diabetes Mellitus; Family Health; Female; Humans; Infant; Kidney; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Proteinuria; Ubiquinone

Topics: Animals; Autophagy; Blotting, Western; Cell Survival; Disease Models, Animal; Flow Cytometry; Mice; Mitochondria, Muscle; Mitochondrial Diseases; Oxidative Stress; Physical Conditioning, Animal; Ubiquinone

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance.. We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated.. The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected.. The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON.

Topics: Antioxidants; Blindness; DNA Copy Number Variations; DNA, Mitochondrial; Female; Genes, Mitochondrial; Humans; Male; Mitochondria; Mitochondrial Diseases; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Ubiquinone; Visual Acuity

Ndufc2, a subunit of the NADH: ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage. The latter was associated with increased oxidative stress and significant ultrastructural impairment of mitochondrial morphology with a loss of internal cristae. In both models the exposure to stress stimuli, such as high-NaCl concentration or LPS, exacerbated the mitochondrial damage and dysfunction. Resveratrol significantly counteracted the ROS generation. These findings provide additional insights on the role of an altered pattern of mitochondrial structure-function as a cause of human diseases. In particular, they contribute to underscore a potential genetic risk factor for cardiovascular diseases, including stroke.

Topics: Animals; Electron Transport Complex I; Fibroblasts; Humans; Leukocytes, Mononuclear; Metabolism, Inborn Errors; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Protein Subunits; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Stroke; Ubiquinone

Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively. Very unexpectedly, we identify a new response pathway to OXPHOS dysfunction in which the intra-mitochondrial synthesis of coenzyme Q (ubiquinone, Q) and Q levels are profoundly decreased, pointing towards novel possibilities for therapy. Our extensive omics analyses provide a high-quality resource of altered gene expression patterns under severe OXPHOS deficiency comparing several mouse models, that will deepen our understanding, open avenues for research and provide an important reference for diagnosis and treatment.

Topics: Animals; Ataxia; Gene Expression Profiling; Metabolome; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Proteome; Ubiquinone

While Coenzyme Q

Topics: Biological Transport; Cells, Cultured; Fibroblasts; Humans; Liposomes; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Ubiquinone

Primary ubiquinone (UQ) deficiency is an important subset of mitochondrial disease that is caused by mutations in UQ biosynthesis genes. To guide therapeutic efforts we sought to estimate the number of individuals who are born with pathogenic variants likely to cause this disorder. We used the NCBI ClinVar database and literature reviews to identify pathogenic genetic variants that have been shown to cause primary UQ deficiency, and used the gnomAD database of full genome or exome sequences to estimate the frequency of both homozygous and compound heterozygotes within seven genetically-defined populations. We used known population sizes to estimate the number of afflicted individuals in these populations and in the mixed population of the USA. We then performed the same analysis on predicted pathogenic loss-of-function and missense variants that we identified in gnomAD. When including only known pathogenic variants, our analysis predicts 1,665 affected individuals worldwide and 192 in the USA. Adding predicted pathogenic variants, our estimate grows to 123,789 worldwide and 1,462 in the USA. This analysis predicts that there are many undiagnosed cases of primary UQ deficiency, and that a large proportion of these will be in developing regions of the world.

Topics: Ataxia; Databases, Nucleic Acid; Exome; Exome Sequencing; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Ubiquinone

SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while

Topics: Ataxia; Brain; Child; Diagnosis, Differential; Homozygote; Humans; Male; Mitochondrial Diseases; Movement Disorders; Muscle Weakness; Muscle, Skeletal; Mutation; Succinate-CoA Ligases; Ubiquinone

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2

Topics: Alkyl and Aryl Transferases; Animals; Ataxia; Cells, Cultured; Fibroblasts; Humans; Mice; Mice, Knockout; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Quinone Reductases; Sulfides; Ubiquinone

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9

Topics: Animals; Ataxia; Blood Pressure; Cells, Cultured; Cerebrum; Disease Models, Animal; Fibroblasts; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Quinone Reductases; Sulfides; Ubiquinone

Topics: Ataxia; Computer Simulation; DNA Mutational Analysis; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Pedigree; Ubiquinone

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Ubiquinone

Laboratory data interpretation for the assessment of complex biological systems remains a great challenge, as occurs in mitochondrial function research studies. The classical biochemical data interpretation of patients versus reference values may be insufficient, and in fact the current classifications of mitochondrial patients are still done on basis of probability criteria. We have developed and applied a mathematic agglomerative algorithm to search for correlations among the different biochemical variables of the mitochondrial respiratory chain in order to identify populations displaying correlation coefficients >0.95. We demonstrated that coenzyme Q

Topics: Adolescent; Algorithms; Biomarkers; Child; Child, Preschool; Citrate (si)-Synthase; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Infant; Mitochondria, Muscle; Mitochondrial Diseases; Ubiquinone

Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease.. To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease.. Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

Topics: Adolescent; Adult; Aged; Ataxia; Biopsy; Cells, Cultured; Child; Child, Preschool; Chromatography, Liquid; Electron Transport; Female; Fibroblasts; Humans; Infant; Male; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Muscles; Mutation; Spectrophotometry; Tandem Mass Spectrometry; Ubiquinone; Young Adult

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

Topics: Ataxia; Cerebellar Ataxia; Codon, Nonsense; Delayed Diagnosis; Electron Transport Chain Complex Proteins; Fibroblasts; Gene Expression; Homozygote; Humans; Lactic Acid; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Muscle, Skeletal; Skin; Ubiquinone

Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders.. A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed.. All four patients presented with childhood-onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype-phenotype correlation.. ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features.

Topics: Adult; Ataxia; Cerebellar Ataxia; Diagnosis, Differential; Epilepsy; Female; Humans; Male; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Proteins; Muscle Weakness; Mutation; Phenotype; Ubiquinone; Young Adult

The Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with mitochondrial DNA (mtDNA) mutations in patients. We previously demonstrated that carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) suppressed CoQ10 levels and COQ5 protein maturation in human 143B cells.. This study explored the putative COQ protein complex in human cells through two-dimensional blue native-polyacrylamide gel electrophoresis and Western blotting to investigate its status in 143B cells after FCCP treatment and in cybrids harboring the mtDNA mutation that caused myoclonic epilepsy with ragged-red fibers (MERRF) syndrome. Ubiquinol-10 and ubiquinone-10 levels were detected by high-performance liquid chromatography. Mitochondrial energy status, mRNA levels of various PDSS and COQ genes, and protein levels of COQ5 and COQ9 in cybrids were examined.. A high-molecular-weight protein complex containing COQ5, but not COQ9, in the mitochondria was identified and its level was suppressed by FCCP and in cybrids with MERRF mutation. That was associated with decreased mitochondrial membrane potential and mitochondrial ATP production. Total CoQ10 levels were decreased under both conditions, but the ubiquinol-10:ubiquinone-10 ratio was increased in mutant cybrids. The expression of COQ5 was increased but COQ5 protein maturation was suppressed in the mutant cybrids.. A novel COQ5-containing protein complex was discovered in human cells. Its destabilization was associated with reduced CoQ10 levels and mitochondrial energy deficiency in human cells treated with FCCP or exhibiting MERRF mutation.. The findings elucidate a possible mechanism for mitochondrial dysfunction-induced CoQ10 deficiency in human cells.

Topics: Ataxia; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Line; DNA, Mitochondrial; Humans; Membrane Potential, Mitochondrial; MERRF Syndrome; Methyltransferases; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; RNA, Messenger; Ubiquinone

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Topics: Aged; Aged, 80 and over; Ataxia; Case-Control Studies; Cerebellum; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Multiple System Atrophy; Muscle Weakness; Oxidative Stress; Ubiquinone

We evaluated the coenzyme Q₁₀ (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n=72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.

Topics: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mitochondrial Diseases; Muscles; Oxidative Phosphorylation; Prevalence; Skin; Ubiquinone; Young Adult

Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertained each patient's mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health. Regardless of the specific underlying mitochondrial disease, the majority of the survey respondents stated they are or have been on dietary supplements. Most patients take more than four supplements primarily coenzyme Q10, l-carnitine, and riboflavin. The majority of patients taking supplements reported health benefits from the supplements. The onset of perceived benefits was between 2weeks to 3months of initiating intake. Supplements seem to be safe, with only 28% of patients experiencing mild side-effects and only 5.6% discontinuing their intake due to intolerance. Only 9% of patients had insurance coverage for their supplements and when paying out of pocket, 95% of them spend up to $500/month. Despite the use of concomitant therapies (prescribed medications, physical therapy, diet changes and other), 45.5% of patients think that dietary supplements are the only intervention improving their symptoms. Some limitations of this study include the retrospective collection of data probably associated with substantial recall bias, lack of longitudinal follow up to document pre- and post-supplement clinical status and second hand reports by parents for children which may reflect parents' subjective interpretation of symptoms severity and supplements effect rather than real patients' experience. More extensive prospective studies will help further elucidate this topic.

Topics: Carnitine; Child; Dietary Supplements; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Mitochondrial Diseases; Oxidative Stress; Parents; Patients; Surveys and Questionnaires; Ubiquinone

COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q

Topics: Alkyl and Aryl Transferases; Ataxia; Gene Expression Regulation; Genotype; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutant Proteins; Mutation; Saccharomyces cerevisiae; Severity of Illness Index; Ubiquinone

Two independent investigations based on the power of yeast genetics, but using radically different discovery-driven approaches, have solved a long-pursued goal: the understanding of the early steps in CoQ biosynthesis, which may help diagnose CoQ deficiencies of unknown origin (Payet et al., 2016; Stefely et al., 2016).

Topics: Ataxia; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Topics: Acidosis, Lactic; Alkyl and Aryl Transferases; Ataxia; Consanguinity; Fatal Outcome; Female; Gene Expression; Hepatic Insufficiency; Humans; Infant, Newborn; Intellectual Disability; Mitochondria, Muscle; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Point Mutation; Proteinuria; Renal Aminoacidurias; Sequence Analysis, DNA; Ubiquinone

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.

Topics: Adipose Tissue, Brown; Animals; Ataxia; CD36 Antigens; Chromatography, High Pressure Liquid; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Oxidation-Reduction; Palmitic Acid; Thermogenesis; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

Topics: Amino Acid Sequence; Ataxia; Base Sequence; Exome; Fatal Outcome; Female; Gene Components; Humans; Male; Mitochondrial Diseases; Mitochondrial Proteins; Molecular Sequence Data; Muscle Weakness; Mutation; Pedigree; Phenotype; Saccharomyces cerevisiae; Sequence Analysis, DNA; Ubiquinone

Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II-IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination.

Topics: Carnitine; Child Development Disorders, Pervasive; Child, Preschool; Female; Folic Acid; Humans; Hyperlactatemia; Infant; Intellectual Disability; Male; Mitochondrial Diseases; Ubiquinone; Vitamins

Mitochondrial respiratory chain (MRC) disorders, defined as primary diseases of the oxidative phosphorylation system, are a protean group of metabolic disorders, difficult to diagnose and classify. The diagnosis is complex and requires the integration of information obtained by clinical, laboratory testing, imaging and muscle biopsy. They may be associated with endocrine disorders, including hypothyroidism, diabetes mellitus, hyperinsulinemia and growth hormone (GH) deficiency.. We describe a case of five years old male with polymalformative syndrome with a systemic involvement. At 6 months of age, he was sent to metabolic consultation because of facial dysmorphy and short stature. During the investigation it was diagnosed at the boy a growth hormone deficiency and because of his multisystemic involvement, muscle biopsy was carried out and showed reduced activity of complex II (38%) of the mitochondrial respiratory chain. Currently, the boy is under GH therapy with growth in the 5th percentile and coenzime Q10.. Mitochondrial biology is one of the fastest growing areas in genetics and medicine. Disturbances in mitochondrial metabolism are now known to play a role not only in rare childhood diseases, but also in many common diseases of aging. In mitochondrial disorders, short stature is a common symptom, but its underlying lesion, growth hormone deficiency, is rarely investigated.

Topics: Child, Preschool; Dwarfism, Pituitary; Human Growth Hormone; Humans; Male; Mitochondrial Diseases; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Topics: Animals; Ataxia; Disease Models, Animal; Genetic Variation; Genotype; Hydroxybenzoates; Mammals; Mice; Mice, Transgenic; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; Ubiquinone

Coenzyme Q10 (CoQ10) is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases, and patients can benefit from CoQ10 supplementation, being more effective when diagnosed and treated early. Due to the increased interest in CoQ10 deficiency, several methods for CoQ10 analysis from plasmatic, muscular, fibroblast, and platelet matrices have been developed. These sampling techniques are not only highly invasive but also too traumatic for periodic clinical monitoring. In the present work, we describe the development and validation of a novel non-invasive sampling method for quantification of CoQ10 in buccal mucosa cells (BMCs) by microHPLC. This method is suitable for using in a routine laboratory and useful for sampling patients in pediatry. CoQ10 correlation was demonstrated between BMCs and plasma levels (Spearman r, 0.4540; p < 0.001). The proposed method is amenable to be applied in the post treatment monitoring, especially in pediatric patients as a non-invasive sample collection. More studies are needed to assess whether this determination could be used for diagnosis and if this matrix could replace the traditional ones.

Topics: Adult; Ataxia; Child; Chromatography, High Pressure Liquid; Humans; Limit of Detection; Mitochondrial Diseases; Mouth Mucosa; Muscle Weakness; Ubiquinone

Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.. We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples.. We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.. We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.

Topics: Amino Acid Sequence; Ataxia; Child; Child, Preschool; Chromatography, Liquid; DNA Mutational Analysis; Exome; Homozygote; Humans; Hydroxybenzoates; Infant, Newborn; Male; Mitochondria; Mitochondrial Diseases; Molecular Sequence Data; Muscle Weakness; Mutation, Missense; Sequence Alignment; Tandem Mass Spectrometry; Ubiquinone

Topics: Adult; Ataxia; Electron-Transferring Flavoproteins; Humans; Iron-Sulfur Proteins; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Ubiquinone; Young Adult

S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.

Topics: Amino Acid Sequence; Amino Acid Transport Systems; Calcium-Binding Proteins; Child, Preschool; DNA Methylation; Female; Humans; Male; Mitochondrial Diseases; Molecular Sequence Data; Muscle Weakness; Mutation; Pedigree; Prognosis; RNA Stability; S-Adenosylmethionine; Sequence Homology, Amino Acid; Thioctic Acid; Ubiquinone

Primary coenzyme Q₁₀ (CoQ₁₀) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ₁₀ supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ₁₀ deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ₁₀. We developed a non-radioactive methodology for the quantification of CoQ₁₀ biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 μmol/L (2)H₃-mevalonate or 1.65 mmol/L (13)C₆-p-hydroxybenzoate. The newly synthesized (2)H₃- and (13)C₆- labelled CoQ₁₀ were analysed by high performance liquid chromatography-tandem mass spectrometry. The mean and the reference range for (13)C₆-CoQ₁₀ and (2)H₃-CoQ₁₀ biosynthesis were 0.97 (0.83-1.1) and 0.13 (0.09-0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ₁₀ deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients' fibroblasts and nine showed decreased CoQ₁₀ biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non-invasive non-radioactive method suitable for the detection of defects in CoQ₁₀ biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.

Topics: Ataxia; Cell Line; Chromatography, High Pressure Liquid; Citrate (si)-Synthase; Fibroblasts; Genotype; Humans; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Mutation; Phenotype; Reference Values; Reproducibility of Results; Skin; Tandem Mass Spectrometry; Time Factors; Ubiquinone

Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ). Mutations in COQ6 cause primary CoQ deficiency, a condition responsive to oral CoQ10 supplementation. Treatment is however still problematic given the poor bioavailability of CoQ10. We employed S. cerevisiae lacking the orthologous gene to characterize the two different human COQ6 isoforms and the mutations found in patients. COQ6 isoform a can partially complement the defective yeast, while isoform b, which lacks part of the FAD-binding domain, is inactive but partially stable, and could have a regulatory/inhibitory function in CoQ10 biosynthesis. Most mutations identified in patients, including the frameshift Q461fs478X mutation, retain residual enzymatic activity, and all patients carry at least one hypomorphic allele, confirming that the complete block of CoQ biosynthesis is lethal. These mutants are also partially stable and allow the assembly of the CoQ biosynthetic complex. In fact treatment with two hydroxylated analogues of 4-hydroxybenzoic acid, namely, vanillic acid or 3-4-hydroxybenzoic acid, restored the respiratory growth of yeast Δcoq6 cells expressing the mutant huCOQ6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients.

Topics: Amino Acid Sequence; Aminobenzoates; Ataxia; Gene Expression; Humans; Hydroxybenzoates; Mitochondria; Mitochondrial Diseases; Models, Molecular; Molecular Sequence Data; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquinone; Vanillic Acid

Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis.. Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP.. Vitamin E γ-tocopherol levels (μmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (μmol/mol) (β = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02).. The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.

Topics: Aged; Ataxia; Cross-Sectional Studies; Diphosphonates; Estrogen Replacement Therapy; Female; Humans; Mitochondrial Diseases; Muscle Weakness; Nitrogen; Osteoporosis, Postmenopausal; Postmenopause; Prognosis; Ubiquinone; Vitamin E; Vitamin E Deficiency

Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms that are common complaints in almost every chronic disease. At the molecular level, a reduction in mitochondrial function occurs as a result of the following changes: (1) a loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations in the function of the electron transport chain, or (3) a reduction in the transport of critical metabolites into mitochondria. In turn, these changes result in a reduced efficiency of oxidative phosphorylation and a reduction in production of adenosine-5'-triphosphate (ATP). Several components of this system require routine replacement, and this need can be facilitated with natural supplements. Clinical trials have shown the utility of using oral replacement supplements, such as L-carnitine, alpha-lipoic acid (α-lipoic acid [1,2-dithiolane-3-pentanoic acid]), coenzyme Q10 (CoQ10 [ubiquinone]), reduced nicotinamide adenine dinucleotide (NADH), membrane phospholipids, and other supplements. Combinations of these supplements can reduce significantly the fatigue and other symptoms associated with chronic disease and can naturally restore mitochondrial function, even in long-term patients with intractable fatigue.

Topics: Carnitine; Dietary Supplements; Fatigue Syndrome, Chronic; Humans; Mitochondrial Diseases; NAD; Thioctic Acid; Ubiquinone

Primary Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with a heterogeneous clinical presentation. Common presenting features include both muscle and neurological dysfunction. Muscle abnormalities can improve, both clinically and biochemically following CoQ10 supplementation, however neurological symptoms are only partially ameliorated. At present, the reasons for the refractory nature of the neurological dysfunction remain unknown. In order to investigate this at the biochemical level we evaluated the effect of CoQ10 treatment upon a previously established neuronal cell model of CoQ10 deficiency. This model was established by treatment of human SH-SY5Y neuronal cells with 1 mM para-aminobenzoic acid (PABA) which induced a 54% decrease in cellular CoQ10 status. CoQ10 treatment (2.5 μM) for 5 days significantly (p<0.0005) decreased the level of mitochondrial superoxide in the CoQ10 deficient neurons. In addition, CoQ10 treatment (5 μM) restored mitochondrial membrane potential to 90% of the control level. However, CoQ10 treatment (10 μM) was only partially effective at restoring mitochondrial electron transport chain (ETC) enzyme activities. ETC complexes II/III activity was significantly (p<0.05) increased to 82.5% of control levels. ETC complexes I and IV activities were restored to 71.1% and 77.7%, respectively of control levels. In conclusion, the results of this study have indicated that although mitochondrial oxidative stress can be attenuated in CoQ10 deficient neurons following CoQ10 supplementation, ETC enzyme activities appear partially refractory to treatment. Accordingly, treatment with >10 μM CoQ10 may be required to restore ETC enzyme activities to control level. Accordingly, these results have important implication for the treatment of the neurological presentations of CoQ10 deficiency and indicate that high doses of CoQ10 may be required to elicit therapeutic efficacy.

Topics: Ataxia; Cell Line, Tumor; Dietary Supplements; DNA, Mitochondrial; Electron Transport; Energy Metabolism; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Neuroblastoma; Neurons; Oxidative Stress; Reactive Oxygen Species; Ubiquinone

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O&NS-mediated damage to fatty acids, DNA and proteins, autoimmune reactions directed against neoantigens and brain disorders. Mitochondrial dysfunctions have been found in ME/cfs, e.g. lowered ATP production, impaired oxidative phosphorylation and mitochondrial damage. This paper reviews the pathways that may explain mitochondrial dysfunctions in ME/cfs. Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways. Therefore, it may be concluded that immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/cfs. Defects in ATP production and the electron transport complex, in turn, are associated with an elevated production of superoxide and hydrogen peroxide in mitochondria creating adaptive and synergistic damage. It is argued that mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in part the central metabolic abnormalities observed in ME/cfs, e.g. glucose hypometabolism and cerebral hypoperfusion.

Topics: Adenosine Triphosphate; Antioxidants; Biomarkers; Brain; Cytokines; Energy Metabolism; Fatigue Syndrome, Chronic; Glucose; Humans; Inflammation; Magnesium; Mitochondria; Mitochondria, Muscle; Mitochondrial Diseases; Neuroimaging; Neuroimmunomodulation; NF-kappa B; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Phenotype; Reactive Nitrogen Species; Reactive Oxygen Species; Ubiquinone; Vitamins

Coenzyme Q10 (CoQ10) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9(X/X)) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. Our results show that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9(X/X) mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum-striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and neurodegenerative diseases.

Topics: Animals; Ataxia; Brain Diseases; Brain Stem; Corpus Striatum; Electron Transport; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Muscle Weakness; Oxidative Stress; Ubiquinone

Large-scale phenotyping projects such as the Sanger Mouse Genetics project are ongoing efforts to help identify the influences of genes and their modification on phenotypes. Gene-phenotype relations are crucial to the improvement of our understanding of human heritable diseases as well as the development of drugs. However, given that there are ∼: 20 000 genes in higher vertebrate genomes and the experimental verification of gene-phenotype relations requires a lot of resources, methods are needed that determine good candidates for testing.. In this study, we applied an association rule mining approach to the identification of promising secondary phenotype candidates. The predictions rely on a large gene-phenotype annotation set that is used to find occurrence patterns of phenotypes. Applying an association rule mining approach, we could identify 1967 secondary phenotype hypotheses that cover 244 genes and 136 phenotypes. Using two automated and one manual evaluation strategies, we demonstrate that the secondary phenotype candidates possess biological relevance to the genes they are predicted for. From the results we conclude that the predicted secondary phenotypes constitute good candidates to be experimentally tested and confirmed.. The secondary phenotype candidates can be browsed through at http://www.sanger.ac.uk/resources/databases/phenodigm/gene/secondaryphenotype/list.. ao5@sanger.ac.uk or ds5@sanger.ac.uk. Supplementary data are available at Bioinformatics online.

Topics: Animals; Ataxia; Data Mining; Disease; Genes; Humans; Mice; Mitochondrial Diseases; Muscle Weakness; Phenotype; Ubiquinone

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

Topics: Adolescent; Adult; Anoctamins; Ataxia; Child; Female; Humans; Membrane Proteins; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone; Young Adult

Coenzyme Q10 (CoQ10) deficiency can manifest diversely, from isolated myopathy to multisystem involvement. Immune dysregulation has not been reported as a feature of the disease. We report a four-year old girl with failure to thrive, recurrent infections, developmental delay with hypotonia, and CoQ10 deficiency with impaired immune function, which improved after CoQ10 and immunoglobulin replacement therapy. Immune dysfunction in CoQ10 deficiency should be considered and treated appropriately.

Topics: Ataxia; Child, Preschool; Enzyme Replacement Therapy; Female; Humans; Immunity; Immunoglobulin G; Lymphocyte Subsets; Mitochondrial Diseases; Muscle Weakness; Treatment Outcome; Ubiquinone

It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient.. We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls.. Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.

Topics: Adolescent; Ataxia; Cation Transport Proteins; Diet, Ketogenic; Dietary Supplements; Female; Glucose Transporter Type 1; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Ubiquinone; Vitamins

Mitochondrial medicine is an evolving discipline whose importance derives from the central function of mitochondria in adenosine triphosphate (ATP) production, generation of reactive oxygen species, and cell death by necrosis or apoptosis. Consequently, mitochondrial dysfunction plays an important role in the progression of aging and the pathophysiology of many common diseases and off-target drug effects. This provides an impetus for the development of mitochondrial pharmacology, and some promising therapeutic targets for mitochondrial protective therapy have been identified.

Topics: Adenosine Triphosphate; Animals; Humans; Mitochondria; Mitochondrial Diseases; Reactive Oxygen Species; Ubiquinone

Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable.. We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values.. Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P < 0.0001). A type 2C fiber frequency of ≥ 5% had 89% sensitivity and 84% specificity for CoQ10 deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ10-deficient patients than in controls.. When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ10 deficiency.

Topics: Abnormalities, Multiple; Ataxia; Child; Child, Preschool; Female; Humans; Incidence; Infant; Male; Mitochondrial Diseases; Muscle Fibers, Fast-Twitch; Muscle Weakness; Quadriceps Muscle; Retrospective Studies; Sensitivity and Specificity; Ubiquinone

We evaluated coenzyme Q₁₀ (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.001). Our findings suggest that MDS are frequently associated with CoQ deficiency, as a possible secondary consequence of disease pathophysiology. Assessment of muscle CoQ status seems advisable in MDS patients since the possibility of CoQ supplementation may then be considered as a candidate therapy.

Topics: Adolescent; Ataxia; Child; Child, Preschool; Chromatography, High Pressure Liquid; DNA, Mitochondrial; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Mitochondrial Diseases; Mitochondrial Myopathies; Muscle Weakness; Muscular Diseases; Real-Time Polymerase Chain Reaction; Ubiquinone; Young Adult

Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.

Topics: Ataxia; Child, Preschool; Electron Transport Complex I; Exome; Female; Genetic Variation; Genome, Mitochondrial; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Leigh Disease; Mitochondria; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Pedigree; Sequence Analysis, DNA; Sequence Analysis, RNA; Ubiquinone

Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid β-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment.

Topics: Acyl Coenzyme A; Ataxia; Bacterial Proteins; Cells, Cultured; Electron-Transferring Flavoproteins; Fibroblasts; Genetic Variation; Humans; Iron-Sulfur Proteins; Mitochondria; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Oxidation-Reduction; Oxidative Stress; Oxidoreductases Acting on CH-NH Group Donors; Reactive Oxygen Species; Rhodobacter sphaeroides; Riboflavin; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life.. An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage.. At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2.. In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.

Topics: Alkyl and Aryl Transferases; Ataxia; Cardiomyopathy, Hypertrophic; Diffusion Magnetic Resonance Imaging; Electroencephalography; Epilepsies, Myoclonic; Genetic Testing; Humans; Infant; Kidney; Magnetic Resonance Spectroscopy; Male; Microscopy, Electron, Transmission; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Mutation; Nephrotic Syndrome; Ubiquinone

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ.

Topics: Alleles; Animals; Ataxia; Cell Respiration; Cell Survival; Disease Models, Animal; Electron Transport; Liver; Membrane Proteins; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mixed Function Oxygenases; Muscle Weakness; Oxygen Consumption; Ubiquinone; Vitamin K 2

A 22-year-old man without pre-existing medical conditions presented to our hospital with a progressive reduction of his physical overall performance, muscle weakness of the extremities, and diarrhea for the last 2 months concomitant with elevated liver enzymes and creatine kinase activity. After ruling out infectious diseases, neoplasia, and autoimmune disorders as a cause of these symptoms, the histology of liver and muscle samples led us to suspect a diagnosis of a rare lipid metabolism disorder. Molecular biologic testing provided the diagnosis of multiple acyl-coA dehydrogenase deficiency with ubiquinone deficiency and late onset. The course of disease was complicated by liver failure and severe pneumonia requiring ventilatory assistance. With the substitution of riboflavin and ubiquinone, the patient showed a gradual recovery of his clinical presentation and an improvement of his laboratory tests. A congenital lipid metabolic disorder might be a rare cause of severe myopathy and hepatopathy in a young adult.

Topics: Adult; Ataxia; Diagnosis, Differential; Humans; Liver Failure; Male; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Riboflavin; Treatment Outcome; Ubiquinone

Topics: Child; DNA, Mitochondrial; Humans; Male; Micronutrients; Mitochondrial Diseases; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree; Polymerase Chain Reaction; Siblings; Treatment Outcome; Ubiquinone; Visual Acuity; Visual Fields

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

Topics: 4-Aminobenzoic Acid; Adenosine Triphosphate; Ataxia; Cell Line, Tumor; Cerebellar Ataxia; DNA, Mitochondrial; Electron Transport; Energy Metabolism; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases; Muscle Weakness; Oxidative Stress; Ubiquinone

Topics: Animals; Humans; Mitochondrial Diseases; Ubiquinone

Mitochondria are essential organelles with multiple functions, the most well known being the production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The mitochondrial diseases are defined by impairment of OXPHOS. They are a diverse group of diseases that can present in virtually any tissue in either adults or children. Here we review the main molecular mechanisms of mitochondrial diseases, as presently known. A number of disease-causing genetic defects, either in the nuclear genome or in the mitochondria's own genome, mitochondrial DNA (mtDNA), have been identified. The most classical genetic defect causing mitochondrial disease is a mutation in a gene encoding a structural OXPHOS subunit. However, mitochondrial diseases can also arise through impaired mtDNA maintenance, defects in mitochondrial translation factors, and various more indirect mechanisms. The putative consequences of mitochondrial dysfunction on a cellular level are discussed.

Topics: Adenosine Triphosphate; Adult; Child; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Myopathies; Oxidative Phosphorylation; Ubiquinone

Amitriptyline is a commonly prescribed tricyclic antidepressant, which has been shown to impair mitochondrial function and increase oxidative stress in a variety of in vitro assays. Coenzyme Q(10) (CoQ(10)), an essential component of the mitochondrial respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In order to evaluate the putative mitochondrial toxicity of amitriptyline, we have analyzed CoQ(10) and ATP levels, oxidative damage and mitochondrial mass in peripheral blood cells from control healthy volunteers and psychiatric patients with depressive episodes treated or non-treated with amitriptyline. In patients not following amitriptyline treatment, CoQ(10) and ATP levels and mitochondrial mass were reduced when compared to normal individuals while lipid peroxidation was clearly increased. All these alterations were aggravated in patients following oral amitriptyline therapy. These results suggest that mitochondrial dysfunction could be involved in the pathophysiology of depression and may be worsened by amitriptyline treatment. CoQ(10) supplementation is postulated to counteract the adverse effects of amitriptyline treatment in psychiatric patients.

Topics: Adenosine Triphosphate; Administration, Oral; Adult; Amitriptyline; Antidepressive Agents, Tricyclic; Antioxidants; Avitaminosis; Biomarkers; Depressive Disorder; Dietary Supplements; Female; Humans; Male; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Ubiquinone

Topics: Adult; Deafness; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Epilepsy; Female; Genes, Mitochondrial; Hearing Loss, Bilateral; Hearing Loss, Conductive; Hearing Loss, Mixed Conductive-Sensorineural; Humans; Hypoglycemia; Insulin; Mitochondrial Diseases; Mutation, Missense; Pedigree; Polymorphism, Restriction Fragment Length; RNA, Transfer, Leu; Ubiquinone

To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures.. Open-label clinical trial.. University medical center. Patients  Five patients with genetically confirmed LHON with acute loss of vision were consecutively enrolled and treated with the experimental therapeutic agent EPI-743 within 90 days of conversion. Intervention  During the course of the study, 5 consecutive patients received EPI-743, by mouth, 3 times daily (100-400 mg per dose).. Treatment effect was assessed by serial measurements of anatomic and functional visual indices over 6 to 18 months, including Snellen visual acuity, retinal nerve fiber layer thickness measured by optical coherence tomography, Humphrey visual fields (mean decibels and area with 1-log unit depression), and color vision. Treatment effect in this clinical proof of principle study was assessed by comparison of the prospective open-label treatment group with historical controls.. Of 5 subjects treated with EPI-743, 4 demonstrated arrest of disease progression and reversal of visual loss. Two patients exhibited a total recovery of visual acuity. No drug-related adverse events were recorded.. In a small open-label trial, EPI-743 arrested disease progression and reversed vision loss in all but 1 of the 5 consecutively treated patients with LHON. Given the known natural history of acute and rapid progression of LHON resulting in chronic and persistent bilateral blindness, these data suggest that the previously described irreversible priming to retinal ganglion cell loss may be reversed.

Topics: Adolescent; Blindness; Child; Chromatography, High Pressure Liquid; Color Vision; Drug Approval; Emergency Medical Services; Eye; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mitochondrial Diseases; Optic Atrophy, Hereditary, Leber; Retina; Tandem Mass Spectrometry; Tomography, Optical Coherence; Ubiquinone; United States; United States Food and Drug Administration; Visual Acuity; Visual Field Tests; Young Adult

Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far. Using a panel of 70 quinones, we observed that the capacity for this cellular energy rescue as well as their effect on lipid peroxidation was influenced more by the physicochemical properties (in particular logD) of the whole molecule than the quinone moiety itself. Thus, the observed correlations allow us to explain the differential biological activities and therapeutic potential of short-chain quinones for the therapy of disorders associated with mitochondrial complex I dysfunction and/or oxidative stress.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Cell Line; Chemical Phenomena; Electron Transport Complex I; Humans; Lipid Peroxidation; Mitochondrial Diseases; Rats; Ubiquinone

While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.

Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Oxidation-Reduction; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ubiquinone; Young Adult

The current study evaluated 23 children (ages 2-16 years) with recurrent food intolerance and allergies for CoQ10 deficiency and mitochondrial abnormalities. Muscle biopsies were tested for CoQ10 levels, pathology, and mitochondrial respiratory chain (MRC) activities. Group 2 (age >10 years; n = 9) subjects had significantly decreased muscle CoQ10 than Group 1 (age <10 y; n = 14) subjects (p = 0.001) and 16 controls (p<0.05). MRC activities were significantly lower in Group 2 than in Group 1 (p<0.05). Muscle CoQ10 levels in study subjects were significantly correlated with duration of illness (adjusted r(2) = 0.69; p = 0.012; n = 23). Children with recurrent food intolerance and allergies may acquire CoQ10 deficiency with disease progression.

Topics: Adolescent; Child; Child, Preschool; Electron Transport; Eosinophilia; Female; Food Hypersensitivity; Gastrointestinal Diseases; Humans; Male; Mitochondria; Mitochondrial Diseases; Quadriceps Muscle; Ubiquinone

Mitochondrial disorders are often associated with primary or secondary CoQ10 decrease. In clinical practice, Coenzyme Q10 (CoQ10) levels are measured to diagnose deficiencies and to direct and monitor supplemental therapy. CoQ10 is reduced by complex I or II and oxidized by complex III in the mitochondrial respiratory chain. Therefore, the ratio between the reduced (ubiquinol) and oxidized (ubiquinone) CoQ10 may provide clinically significant information in patients with mitochondrial electron transport chain (ETC) defects. Here, we exploit mutants of Caenorhabditis elegans (C. elegans) with defined defects of the ETC to demonstrate an altered redox ratio in Coenzyme Q9 (CoQ9), the native quinone in these organisms. The percentage of reduced CoQ9 is decreased in complex I (gas-1) and complex II (mev-1) deficient animals, consistent with the diminished activity of these complexes that normally reduce CoQ9. As anticipated, reduced CoQ9 is increased in the complex III deficient mutant (isp-1), since the oxidase activity of the complex is severely defective. These data provide proof of principle of our hypothesis that an altered redox status of CoQ may be present in respiratory complex deficiencies. The assessment of CoQ10 redox status in patients with mitochondrial disorders may be a simple and useful tool to uncover and monitor specific respiratory complex defects.

Topics: Animals; Antioxidants; Caenorhabditis elegans; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Humans; Mitochondria; Mitochondrial Diseases; Oxidation-Reduction; Ubiquinone

The role of a secondary respiratory chain deficiency as an additional mechanism to intoxication, leading to development of long-term energy-dependent complications, has been recently suggested in patients with propionic acidemia (PA). We show for the first time a coenzyme Q(10) (CoQ(10)) functional defect accompanied by a multiple organ oxidative phosphorylation (OXPHOS) deficiency in a child who succumbed to acute heart failure in the absence of metabolic stress. Quinone-dependent activities in the liver (complex I+III, complex II+III) were reduced, suggesting a decrease in electron transfer related to the quinone pool. The restoration of complex II+III activity after addition of exogenous ubiquinone to the assay system suggests CoQ(10) deficiency. Nevertheless, we disposed of insufficient material to perform direct measurement of CoQ(10) content in the patient's liver. Death occurred before biochemical diagnosis of OXPHOS deficiency could be made. However, this case highlights the usefulness of rapidly identifying CoQ(10) defects secondary to PA since this OXPHOS disorder has a good treatment response which could improve heart complications or prevent their appearance. Nevertheless, further studies will be necessary to determine whether CoQ(10) treatment can be useful in PA complications linked to CoQ(10) deficiency.

Topics: Child; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Heart Failure; Humans; Liver; Male; Mitochondrial Diseases; Propionic Acidemia; Ubiquinone

Although mitochondrial disease research in general is robust, adequate treatment of these life-threatening conditions has lagged, partly because of a persistence of clinical anecdotes as substitutes for scientifically and ethically rigorous clinical trials. Here I summarize the key lessons learned from some of the "first generation" of randomized controlled trials for genetic mitochondrial diseases and suggest how future trials may benefit from both past experience and exciting new resources available for patient-oriented research and training in this field.

Topics: Acidosis, Lactic; Animals; Dichloroacetic Acid; Financing, Government; Humans; MELAS Syndrome; Mitochondrial Diseases; Neglected Diseases; Randomized Controlled Trials as Topic; Rare Diseases; Societies, Medical; Ubiquinone; United States

Vitamin A supplementation among women is a common habit worldwide in an attempt to slow aging progression due to the antioxidant potential attributed to retinoids. Nonetheless, vitamin A elicits a myriad of side effects that result from either therapeutic or inadvertent intake at varying doses for different periods. The mechanism behind such effects remains to be elucidated. In this regard, we performed the present work aiming to investigate the effects of vitamin A supplementation at 100, 200, or 500IU/kgday(-1) for 2 months on female rat brain, analyzing tissue lipid peroxidation levels, antioxidant enzyme activities (both Cu/Zn-superoxide dismutase - SOD - and Mn-SOD); glutathione S-transferase (GST) and monoamine oxidase (MAO) enzyme activity; mitochondrial respiratory chain activity and redox parameters in mitochondrial membranes, as well as quantifying α- and β-synucleins, β-amyloid peptide(1-40), immunoglobulin heavy-chain binding protein/78kDa glucose-regulated protein (BiP/GRP78), receptor for advanced glycation end products (RAGE), D2 receptor, and tumor necrosis factor-α (TNF-α) contents in rat frontal cortex, hippocampus, striatum, and cerebellum. We observed increased lipid peroxidation marker levels, altered Cu/Zn-SOD and Mn-SOD enzyme activities, mitochondrial nitrosative stress, and impaired respiratory chain activity in such brain regions. On the other hand, we did not find any change in MAO and GST enzyme activities, and on α- and β-synucleins, β-amyloid peptide(1-40), GRP78/BiP, RAGE, D2 receptor, and TNF-α contents. Importantly, we did not observed any evidence regarding an antioxidant effect of such vitamin at low doses in this experimental model. The use of vitamin A as an antioxidant therapy among women needs to be reexamined.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Brain Chemistry; Electron Transport; Enzyme-Linked Immunosorbent Assay; Estrous Cycle; Female; Glycation End Products, Advanced; Mitochondrial Diseases; Mitochondrial Membranes; Monoamine Oxidase; Oxidative Stress; Rats; Rats, Wistar; Receptors, Dopamine D2; Succinate Dehydrogenase; Superoxide Dismutase; Synucleins; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquinone; Vitamin A; Vitamins

To investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Alzheimer's disease (AD), we employed high-performance liquid chromatography using an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q-10 (CoQ-10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 30 patients with AD and in 30 age-matched controls with no neurological disease. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF of the AD group (78.2 +/- 18.8%) was significantly higher than in the control group (41.3 +/- 10.4%) (P < 0.0001). The concentration of 8-OHdG in the CSF of AD patients was greater than in the CSF of controls (P < 0.0001) and was positively correlated with the duration of illness (r(s) = 0.95, P < 0.0001). The %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of AD patients (r(s) = 0.66, P < 0.001). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early AD development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain; Brain Chemistry; Deoxyguanosine; DNA Damage; Female; Free Radicals; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Nerve Degeneration; Oxidative Stress; Ubiquinone

Microarray expression profiling has become a valuable tool in the evaluation of the genetic consequences of metabolic disease. Although 3'-biased gene expression microarray platforms were the first generation to have widespread availability, newer platforms are gradually emerging that have more up-to-date content and/or higher cost efficiency. Deciphering the relative strengths and weaknesses of these various platforms for metabolic pathway-level analyses can be daunting. We sought to determine the practical strengths and weaknesses of four leading commercially available expression array platforms relative to biologic investigations, as well as assess the feasibility of cross-platform data integration for purposes of biochemical pathway analyses.. Liver RNA from B6.Alb/cre,Pdss2(loxP/loxP) mice having primary coenzyme Q deficiency was extracted either at baseline or following treatment with an antioxidant/antihyperlipidemic agent, probucol. Target RNA samples were prepared and hybridized to Affymetrix 430 2.0, Affymetrix Gene 1.0 ST, Affymetrix Exon 1.0 ST, and Illumina Mouse WG-6 expression arrays. Probes on all platforms were re-mapped to coding sequences in the current version of the mouse genome. Data processing and statistical analysis were performed by R/Bioconductor functions, and pathway analyses were carried out by KEGG Atlas and GSEA.. Expression measurements were generally consistent across platforms. However, intensive probe-level comparison suggested that differences in probe locations were a major source of inter-platform variance. In addition, genes expressed at low or intermediate levels had lower inter-platform reproducibility than highly expressed genes. All platforms showed similar patterns of differential expression between sample groups, with 'steroid biosynthesis' consistently identified as the most down-regulated metabolic pathway by probucol treatment.. This work offers a timely guide for metabolic disease investigators to enable informed end-user decisions regarding choice of expression microarray platform best-suited to specific research project goals. Successful cross-platform integration of biochemical pathway expression data is also demonstrated, especially for well-annotated and highly expressed genes. However, integration of gene-level expression data is limited by individual platform probe design and the expression level of target genes. Cross-platform analyses of biochemical pathway data will require additional data processing and novel computational bioinformatics tools to address unique statistical challenges.

Topics: Animals; Antioxidants; Computational Biology; Disease Models, Animal; Gene Expression Profiling; Mice; Mice, Knockout; Mitochondrial Diseases; Oligonucleotide Array Sequence Analysis; Probucol; Proteins; RNA; Treatment Outcome; Ubiquinone

Topics: Brain Diseases, Metabolic; Chronic Disease; Disease Progression; DNA, Mitochondrial; Genetic Predisposition to Disease; Haplotypes; Humans; Migraine Disorders; Mitochondrial Diseases; Riboflavin; Thioctic Acid; Ubiquinone; Vitamin B Complex

The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect.

Topics: Animals; Antioxidants; Cocaine; Cocaine-Related Disorders; Disease Susceptibility; Drug Evaluation, Preclinical; Heart Diseases; Male; Mitochondria, Heart; Mitochondrial Diseases; Molecular Targeted Therapy; Organophosphorus Compounds; Oxygen Consumption; Rats; Rats, Wistar; Reactive Oxygen Species; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Signs associated with skin alteration and mitochondrial dysfunction have been observed in patients with fibromyalgia (FM). The aim of this study was to analyze CoQ(10) levels, mitochondrial dysfunction, and oxidative stress in plasma, blood mononuclear cells, and skin biopsies from FM patients.. We studied CoQ(10) level by HPLC in plasma, blood mononuclear cells, and skin obtained from patients with FM and healthy control subjects. Oxidative stress markers and mitochondrial respiratory chain enzyme activities were analysed in both plasma, blood mononuclear cells, and skin biopsies from FM patients.. Oxidative stress, mitochondrial dysfunction, and CoQ(10) deficiency have been observed in blood mononuclear cells and skin biopsies.. In our patients, mitochondrial dysfunction and CoQ(10) deficiency are present in several tissues. These results may contribute to the understanding of the pathophysiology of FM, and, moreover, CoQ(10) deficiency could represent a good marker for the diagnosis of FM.

Topics: Adult; Aged; Biopsy; Blood Cells; Case-Control Studies; Female; Fibromyalgia; Humans; Leukocytes, Mononuclear; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Skin; Ubiquinone

Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.

Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caenorhabditis elegans; Calcium; gamma-Aminobutyric Acid; Mitochondrial Diseases; Neurodegenerative Diseases; Neurons; Ubiquinone

Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drug's potential to improve mitochondrial respiratory chain function and reduce oxidative stress.. In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice.. We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.

Topics: Animals; Antioxidants; Biomarkers; Cardiotonic Agents; Diastole; Dobutamine; Echocardiography; Fibrosis; Male; Mice; Mice, Inbred mdx; Mitochondrial Diseases; Muscle, Skeletal; Muscular Dystrophy, Animal; Myocardium; Oxidative Stress; Physical Conditioning, Animal; Placebos; Single-Blind Method; Time Factors; Troponin I; Ubiquinone

To report on a case with a mitochondrial DNA (mtDNA) depletion syndrome.. Laboratory studies were done in muscle biopsy and fibroblasts to evaluate coenzyme Q(10) (CoQ(10)) status and quantify mitochondrial DNA.. Decreased CoQ(10) values and a 78% of mtDNA depletion were detected in muscle. Mutational studies failed to reveal any pathogenic mutation in nuclear genes related with mtDNA maintenance.. mtDNA depletion syndrome was associated with CoQ(10) deficiency in our patient.

Topics: DNA, Mitochondrial; Female; Humans; Infant, Newborn; Mitochondria, Muscle; Mitochondrial Diseases; Muscle, Skeletal; Ubiquinone

Here we report effect of ischemia-reperfusion on mitochondrial Ca2+ uptake and activity of complexes I and IV in rat hippocampus. By performing 4-vessel occlusion model of global brain ischemia, we observed that 15 min ischemia led to significant decrease of mitochondrial capacity to accumulate Ca2+ to 80.8% of control whereas rate of Ca2+ uptake was not significantly changed. Reperfusion did not significantly change mitochondrial Ca2+ transport. Ischemia induced progressive inhibition of complex I, affecting final electron transfer to decylubiquinone. Minimal activity of complex I was observed 24 h after ischemia (63% of control). Inhibition of complex IV activity to 80.6% of control was observed 1 h after ischemia. To explain the discrepancy between impact of ischemia on rate of Ca2+ uptake and activities of both complexes, we performed titration experiments to study relationship between inhibition of particular complex and generation of mitochondrial transmembrane potential (DeltaPsi(m)). Generation of a threshold curves showed that complex I and IV activities must be decreased by approximately 40, and 60%, respectively, before significant decline in DeltaPsi(m) was documented. Thus, mitochondrial Ca2+ uptake was not significantly affected by ischemia-reperfusion, apparently due to excess capacity of the complexes I and IV. Inhibition of complex I is favourable of reactive oxygen species (ROS) generation. Maximal oxidative modification of membrane proteins was documented 1 h after ischemia. Although enhanced formation of ROS might contribute to neuronal injury, depressed activities of complex I and IV together with unaltered rate of Ca2+ uptake are conditions favourable of initiation of other cell degenerative pathways like opening of mitochondrial permeability transition pore or apoptosis initiation, and might represent important mechanism of ischemic damage to neurones.

Topics: Adaptor Protein Complex 1; Adaptor Protein Complex 4; Animals; Azides; Brain Ischemia; Calcium; Ferricyanides; Hippocampus; Male; Membrane Potentials; Membrane Proteins; Mitochondria; Mitochondrial Diseases; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Rotenone; Spectrometry, Fluorescence; Ubiquinone; Uncoupling Agents

Phenylketonuria (PKU) is an autosomal recessive disorder resulting in neurological and intellectual disability when untreated. However, even in treated patients there may be residual neurological impairment such as tremor. It has been suggested that the hyperphenylalaninaemia in patients with PKU reduces complex I (NADH:ubiquinone reductase) activity of the mitochondrial respiratory chain (MRC) and/or biosynthesis of coenzyme Q(10) (CoQ(10)), which acts as an electron carrier in the MRC, leading to impaired energy metabolism in the brain of patients with PKU and hence the neurological pathology. The aim of this study was to elucidate the mechanism of phenylalanine (Phe) toxicity on the MRC. We compared mean plasma and blood-spot Phe and mononuclear CoQ(10) levels in 17 patients with PKU and a tremor compared to 22 patients without tremor. Human 1321N1 astrocytoma cells were exposed to hyperphenylalaninaemia by the addition of 300 or 900 micromol/L of Phe to the cell culture medium. Following 96 h of culture we measured complex I and citrate synthase activities and CoQ(10) level. Results showed no significant difference in Phe or CoQ(10) levels in patients with tremor compared to those without tremor. Further, hyperphenylalaninaemia did not cause a significant reduction in complex I activity or CoQ(10) biosynthesis, even when taking into account the mitochondrial enrichment of the cell samples by expressing complex I and CoQ(10) as a ratio to citrate synthase. In conclusion, the results of this study suggest that hyperphenylalaninaemia does not contribute to the pathophysiology of PKU by causing a decrease in MRC complex I activity and/or CoQ(10) biosynthesis.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Cell Line, Tumor; Cells, Cultured; Culture Media; Electron Transport; Female; Humans; Lactic Acid; Male; Middle Aged; Mitochondrial Diseases; Phenylalanine; Phenylketonurias; Pyruvic Acid; Tremor; Tyrosine; Ubiquinone; Young Adult

Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q(10) biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q(10) deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth.

Topics: Amino Acid Sequence; Cells, Cultured; Codon, Nonsense; Fibroblasts; Genetic Predisposition to Disease; Homozygote; Humans; Infant; Infant, Newborn; Mitochondrial Diseases; Models, Molecular; Molecular Sequence Data; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Skin; Ubiquinone

Mitochondrial myopathies are regulated by two genomes: the nuclear DNA, and the mitochondrial DNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mitochondrial DNA, a new field of investigation is that of syndromes due to mutations in the nuclear DNA. These latter disorders have mendelian inheritance.. Three representative cases have been selected: one with COX deficiency and a Leigh syndrome due to a SURF1 gene mutation, one due to a defect of Coenzyme Q synthesis and one with dominant optic atrophy due to a mutation in the OPA1 gene.. Future developments will show that many neurodegenerative disorders are due to mutations of nuclear genes controlling mitochondrial function, fusion and fission.

Topics: Cell Nucleus; Child; DNA; Female; Genome; GTP Phosphohydrolases; Humans; Infant; Leigh Disease; Male; Membrane Proteins; Middle Aged; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Optic Atrophy; Prostaglandin-Endoperoxide Synthases; Ubiquinone

The contribution of mitochondrial dysfunction and oxidative stress to the pathogenesis of Alzheimer's disease (AD) has previously been described. We aimed to investigate whether the balance between the oxidized and reduced forms of coenzyme Q-10 (CoQ-10) is related to the pathogenesis of AD.. Thirty patients with AD (69.0 +/- 4.1 years) and 30 healthy control subjects (63.8 +/- 16.4 years) were enrolled in this study. Concentrations of oxidized CoQ-10 and reduced CoQ-10 were measured by high-performance liquid chromatography using an electrochemical detector.. The percentage of oxidized/total CoQ-10 in the cerebrospinal fluid (%CoQ-10, CSF) was significantly higher in the untreated AD group (78.2 +/- 18.8%) than in the control group (41.3 +/- 10.4%, p < 0.001), and there was a significant negative correlation between %CoQ-10 and the duration of the illness (r(s) = -0.93, p < 0.001).. These findings in living AD patients suggest a possible role for %CoQ-10 in the pathogenesis of the early stage of AD development.

Topics: Aged; Alzheimer Disease; Biomarkers; Chromatography, High Pressure Liquid; Disease Progression; Electron Transport; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Oxidation-Reduction; Oxidative Stress; Ubiquinone

To investigate whether mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis (sALS), we used high-performance liquid chromatography with an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q10 (CoQ10) in the cerebrospinal fluid (CSF) of 30 patients with sALS and 17 age-matched controls with no neurological diseases. The percentage of oxidized CoQ10 in the CSF of sALS patients were significantly greater than those in the CSF of controls (P<0.002) and were negatively correlated with duration of illness (rho=-0.64, P<0.001). These results suggest that mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis.

Topics: Adult; Amyotrophic Lateral Sclerosis; Biomarkers; Central Nervous System; Energy Metabolism; Female; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Oxidation-Reduction; Oxidative Stress; Ubiquinone

Activity defects in respiratory chain complexes are responsible for a large variety of pathological situations, including neuromuscular diseases and multisystemic disorders. Their impact on energy production is highly variable and disproportional. The same biochemical or genetic defect can lead to large differences in clinical symptoms and severity between tissues and patients, making the pathophysiological analysis of mitochondrial diseases difficult. The existence of compensatory mechanisms operating at the level of the respiratory chain might be an explanation for the biochemical complexity observed for respiratory defects. Here, we analyzed the role of cytochrome c and coenzyme Q in the attenuation of complex III and complex IV pharmacological inhibition on the respiratory flux. Spectrophotometry, HPLC-EC, polarography and enzymology permitted the calculation of molar ratios between respiratory chain components, giving values of 0.8:61:3:12:6.8 in muscle and 1:131:3:9:6.5 in liver, for CII:CoQ:CIII:Cyt c:CIV. The results demonstrate the dynamic functional compartmentalization of respiratory chain substrates, with the existence of a substrate pool that can be recruited to maintain energy production at normal levels when respiratory chain complexes are inhibited. The size of this reserve was different between muscle and liver, and in proportion to the magnitude of attenuation of each respiratory defect. Such functional compartmentalization could result from the recently observed physical compartmentalization of respiratory chain substrates. The dynamic nature of the mitochondrial network may modulate this compartmentalization and could play a new role in the control of mitochondrial respiration as well as apoptosis.

Topics: Animals; Cytochromes c; Electron Transport; Electron Transport Complex III; Electron Transport Complex IV; Male; Methacrylates; Mitochondria, Liver; Mitochondria, Muscle; Mitochondrial Diseases; Oxygen Consumption; Potassium Cyanide; Rats; Rats, Wistar; Thiazoles; Ubiquinone

The lipophilic antioxidant coenzyme Q10 is an effective inhibitor of oxidative damage. Furthermore coenzyme Q10 is involved in electron transport related to the mitochondrial respiratorial chain. Because of this double function coenzyme Q10 has become a special role in the group of antioxidants. Little is known about coenzyme Q10 in healthy and sick children. The aim of the study was to determine the role of coenzyme Q10 in the pathophysiological concept of pediatric diseases. At first a HPLC-method for the detection of coenzyme Q10 in plasma, erythrocytes and platelets was developed and age-related reference values for children were established. Based on these reference values the CoQ10 status was measured in different pediatric diseases. By this way various conditions for low coenzyme Q10 plasma values in children could be defined. Furthermore there were different in vivo models developed to define pharmacokinetic and pharmacodynamic characteristics of coenzyme Q10. The established methods and measured data might be a helpful contribution for estimating coenzyme Q10 deficiency and for planning therapeutical studies with coenzyme Q10 in childhood.

Topics: Antioxidants; Ataxia; Child; Hepatitis; Humans; Migraine Disorders; Mitochondria, Muscle; Mitochondrial Diseases; Oxidative Stress; Severity of Illness Index; Ubiquinone

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/kd) mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2(loxP/loxP) knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment.

Topics: Alkyl and Aryl Transferases; Animals; Base Sequence; DNA Primers; Electron Transport; Gene Expression Profiling; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mitochondria, Liver; Mitochondrial Diseases; Mutation, Missense; Oligonucleotide Array Sequence Analysis; Phenotype; Ubiquinone

Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and Deltacoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.

Topics: Adolescent; Adult; Alkyl and Aryl Transferases; Amino Acid Sequence; Amino Acid Substitution; Child, Preschool; Chromosomes, Human, Pair 10; Coenzymes; Female; Genetic Complementation Test; Homozygote; Humans; Male; Mitochondrial Diseases; Molecular Sequence Data; Mutation; Oxidative Phosphorylation; Pedigree; Sequence Analysis, DNA; Ubiquinone; Yeasts

Topics: Aged; Biopsy; Carbazoles; Cardiomyopathies; Carvedilol; Coenzymes; Coronary Angiography; Enalapril; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Mitochondria, Heart; Mitochondrial Diseases; Propanolamines; Ubiquinone

The cardiofaciocutaneous (CFC) syndrome is characterized by congenital heart defect, developmental delay, peculiar facial appearance with bitemporal constriction, prominent forehead, downslanting palpebral fissures, curly sparse hair and abnormalities of the skin. CFC syndrome phenotypically overlaps with Noonan and Costello syndromes. Mutations of several genes (PTPN11, HRAS, KRAS, BRAF, MEK1 and MEK2), involved in the mitogen-activated protein kinase (MAPK) pathway, have been identified in CFC-Costello-Noonan patients. Coenzyme Q10 (CoQ10), a lipophilic molecule present in all cell membranes, functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. CoQ10 deficiency is a rare treatable mitochondrial disorder with various neurological (cerebellar ataxia, myopathy, epilepsy, mental retardation) and extraneurological (cardiomyopathy, nephropathy) signs that are responsive to CoQ10 supplementation. We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency. Her psychomotor development was severely impaired, hindered by muscular hypotonia and ataxia, both improving remarkably after CoQ10 treatment. This case suggests that there is a functional connection between the MAPK pathway and the mitochondria. This could be through the phosphorylation of a nuclear receptor essential for CoQ10 biosynthesis. Another hypothesis is that K-Ras, one of the proteins composing the MAPK pathway, might be recruited into the mitochondria to promote apoptosis. This case highlights that CoQ10 might contribute to the pathogenesis of CFC syndrome.

Topics: Abnormalities, Multiple; Child, Preschool; Coenzymes; Craniofacial Abnormalities; Female; Heart Defects, Congenital; Humans; MAP Kinase Signaling System; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Skin Abnormalities; Syndrome; Treatment Outcome; Ubiquinone

Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

Topics: Acute Kidney Injury; Alkyl and Aryl Transferases; Coenzymes; Electron Transport Chain Complex Proteins; Humans; Infant; Kidney; Male; Mitochondrial Diseases; Muscle, Skeletal; Mutation, Missense; Nephrotic Syndrome; Ubiquinone

Autistic disorder is a heterogeneous disorder. The majority of the cases are idiopathic, and only a small number of the autistic children have associated secondary diagnosis. This article reports 2 children with mitochondrial disorders associated with autistic disorder fulfilling the diagnostic criteria of the American Psychiatric Association Manual of Psychiatric Diseases, 4th edition, and briefly reviews the literature on autistic disorder associated with mitochondrial disorders.

Topics: Atrophy; Autistic Disorder; Brain; Brain Chemistry; Brain Diseases, Metabolic, Inborn; Child, Preschool; Female; Humans; Infant; Mitochondria; Mitochondrial Diseases; Ubiquinone

We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.

Topics: Amino Acid Sequence; Base Sequence; Cell Nucleus; Child; Child, Preschool; DNA Mutational Analysis; DNA, Complementary; Electron Transport Complex II; Electrophoresis, Polyacrylamide Gel; Humans; Hypothalamus, Middle; Infant; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Molecular Sequence Data; Mutation; Phenotype; Protein Structure, Secondary; Protein Subunits; Radiography; Ubiquinone

Mutations in mitochondrial DNA are rare etiologies of adult-onset diabetes mellitus (DM) that merit identification to 1) prevent iatrogenic lactic acidosis, 2) prompt appropriate screening of affected patients and their families, 3) provide genetic counseling, and 4) provide an opportunity to investigate strategies for preventing diabetes.. The objective of this study is to raise awareness of this rare form of adult-onset nonobese DM so that these patients are identified and provided with appropriate care.. We describe a kindred in which four of seven siblings have adult-onset DM and sensorineural hearing loss with a confirmed genetic mutation at position 3243 in the tRNA. Two other siblings in this kindred demonstrate different phenotypes of mitochondrial disease.. The proband was treated with coenzyme Q10 for 1 yr.. Outcome measures included stress thallium exercise testing and audiometry testing.. After 1 yr of treatment of with coenzyme Q10, repeat stress thallium testing demonstrated improvement in the exercise tolerance of the proband from 7-12 min. Audiometry testing did not demonstrate a change in the rate of hearing decline.. Maternally inherited diabetes and deafness is a rare cause of DM that is important to diagnose because of the unique management issues and associated comorbidities. This work highlights clues to the identification of this rare monogenic form of adult- onset diabetes.

Topics: Adult; Coenzymes; Diabetes Mellitus, Type 2; Exercise Test; Female; Genes, X-Linked; Hearing Loss, Sensorineural; Humans; Mitochondrial Diseases; Models, Biological; North America; Pedigree; RNA, Transfer, Leu; Ubiquinone

Coenzyme Q (CoQ) has been suggested as a biomarker for tissue redox status. The aims are (1) to compare ubiquinol-9, ubiquinol-10, ubiquinone-9, ubiquinone-10, total CoQ content and CoQ redox ratio in quadriceps muscle, heart, brain and liver tissues of mdx mice with wild-type controls; and (2) to determine if ubiquinol content and CoQ redox ratio changes are associated with pathological findings in mdx mouse.. CoQ contents were determined in homogenized quadriceps muscle, heart, liver and brain of age-matched mdx and wild-type control mice by HPLC-EC. Light and electron microscopy studies were conducted using standard pathology methods.. Ubiquinol-9 and ubiquinol-10 concentrations are significantly increased in quadriceps and heart muscle of mdx mouse. Increased redox ratios of coenzyme Q(9) and coenzyme Q(10) are also evident in quadriceps, heart and liver tissues in mdx mouse, but not brain. Pathological examination shows marked myofiber regeneration and evidence of mitochondrial proliferation for mdx muscle.. Evidence that changes in ubiquinol content and CoQ redox ratio are related to pathological features in mdx skeletal and heart myofibers suggests that tissue ubiquinol content and CoQ redox ratio may be useful biomarkers for evaluating muscle disorders associated with mitochondrial proliferation and defects in oxidative phosphorylation.

Topics: Animals; Biomarkers; Energy Metabolism; Mice; Mice, Mutant Strains; Microscopy, Electron; Mitochondrial Diseases; Muscular Dystrophy, Duchenne; Myofibrils; Oxidation-Reduction; Oxidative Stress; Tissue Distribution; Ubiquinone

Coenzyme Q(10) (CoQ) deficiency syndrome is a disorder of unknown ethiology that may cause different forms of mitochondrial encephalomyopathy. In the present study our aim was to analyse CoQ concentration and mitochondrial respiratory chain (MRC) enzyme activities in muscle biopsies of patients with clinical suspicion and/or biochemical-molecular diagnosis of a mitochondrial disorder. We studied 36 patients classified into 3 groups: 1) 14 patients without a definitive diagnosis of mitochondrial disease, 2) 13 patients with decreased CI + III and II + III activities of the MRC, and 3) 9 patients with definitive diagnosis of mitochondrial disease. Only 1 of the 14 patients of group 1 showed slightly reduced CoQ values in muscle. Six of the 13 patients from group 2 showed partial CoQ deficiency in muscle and 1 of the 9 cases from group 3 presented a slight CoQ deficiency. Significantly positive correlation was observed between CI + III and CII + III activities with CoQ concentrations in the 36 muscle homogenates from patients (r = 0.555; p = 0.001; and r = 0.460; p = 0.005, respectively). In conclusion, measurement of MRC enzyme activities is a useful tool for the detection of CoQ deficiency, which should be confirmed by CoQ quantification.

Topics: Adolescent; Adult; Biopsy; Child; Child, Preschool; Citrate (si)-Synthase; Coenzymes; Humans; Infant; Infant, Newborn; Mitochondrial Diseases; Muscles; NADH Dehydrogenase; Succinate Cytochrome c Oxidoreductase; Ubiquinone

Endogenous oxidative stress is believed to play a key role in the pathogenesis of mitochondrial diseases (MD). In this group of heterogeneous disorders the increased production of radical species caused by compromised mitochondrial respiratory function could affect both mitochondrial and nuclear DNA integrity. The aim of the present study was to assess the basal level of nuclear DNA (nDNA) damage in terms of chromosome and DNA alterations in leukocytes of 13 patients (age range 29-74 years) presenting several forms of MD. A further objective of this work was the evaluation of possible changes in nDNA in a subgroup of patients (10 individuals) before and after a 2 week therapy with ubidecarenone, a coenzyme Q10 analogue. The extent of cytogenetic damage, expressed as chromosome breakage and chromosome loss, was assessed employing the cytokinesis block micronucleus method in cultured peripheral blood lymphocytes, coupled with fluorescence in situ hybridization analysis using a digoxigenin-labelled pancentromeric DNA probe. A modified version of the single cell gel electrophoresis assay was used to quantify primary and oxidative DNA damage in leukocytes. In MD patients an increased level of chromosome damage, expressed as frequency of micronucleated lymphocytes, was detected in comparison with healthy individuals of corresponding sex, age and lifestyle. The FISH analysis revealed a preferential occurrence of micronuclei arising from loss of whole chromosomes in patients, with no substantial difference in frequencies observed in matched controls. The Comet assay indicated a slightly higher level of primary DNA damage in patients compared with controls and also a difference in oxidative DNA damage, however, this was not statistically significant. Patients receiving ubidecarenone showed a statistically significant reduction in the frequency of micronucleated cells after therapy, while only a slight decrease was observed in the levels of both primary DNA damage and oxidized bases.

Topics: Adult; Aged; Cells, Cultured; Coenzymes; Comet Assay; Cytogenetic Analysis; DNA Damage; Female; Humans; In Situ Hybridization, Fluorescence; Leukocytes; Lymphocytes; Male; Micronucleus Tests; Middle Aged; Mitochondrial Diseases; Ubiquinone

We reviewed the medical records of all patients with confirmed mitochondrial diseases treated with any or all of thiamin, riboflavin, coenzyme Q, vitamin C (approximately 10 mg/kg per day) and a high-fat diet (50-60% of caloric intake) between 1997 and 2003. There were 15 patients (9 male): 10 had enzymatic deficiency and 10 had a molecular diagnosis. Age at diagnosis was 11 months to 17 years 10 months. Treatment was commenced at time of clinical diagnosis in 12 patients. Follow-up period was 3 days to 7 years (median 22 months). Improvement was reported in 9 patients, of whom 4 attained further developmental skills, but this was only temporary in 6 patients. Five patients died during the follow-up period (3 days to 7 years). Patients with the 3243A > G mutation showed no significant change in the course of their disease, except for fewer migraine attacks. Of the six patients who had seizures, one has had a significant reduction in the severity of the seizures and one has had no further seizures. Plasma lactate levels were noncontributory. We conclude that high-dose vitamin and cofactor treatment and, where applicable, high-fat diet, are well tolerated and possibly effective in the short term, but ineffective in the longer term.

Topics: Adolescent; Ascorbic Acid; Child; Child, Preschool; Dietary Fats; DNA, Mitochondrial; Female; Humans; Infant; Lactic Acid; Male; Mitochondrial Diseases; Mutation; Riboflavin; Thiamine; Ubiquinone; Vitamins

Topics: Aged; Antioxidants; Coenzymes; Deafness; Diabetes Mellitus, Type 2; DNA Mutational Analysis; DNA, Mitochondrial; Female; Humans; Mitochondrial Diseases; Phenotype; Point Mutation; Ubiquinone

Complex III in the mitochondrial electron transport chain is a proposed site for the enhanced production of reactive oxygen species that contribute to aging in the heart. We describe a defect in the ubiquinol binding site (Q(O)) within cytochrome b in complex III only in the interfibrillar population of cardiac mitochondria during aging. The defect is manifested as a leak of electrons through myxothiazol blockade to reduce cytochrome b and is observed whether cytochrome b in complex III is reduced from the forward or the reverse direction. The aging defect increases the production of reactive oxygen species from the Q(O) site of complex III in interfibrillar mitochondria. A greater leak of electrons from complex III during the oxidation of ubiquinol is a likely mechanism for the enhanced oxidant production from mitochondria that contributes to aging in the rat heart.

Topics: Aging; Animals; Antimycin A; Binding Sites; Cytochrome b Group; Electron Transport; Electron Transport Complex III; Enzyme Activation; Hydroquinones; In Vitro Techniques; Male; Methacrylates; Mitochondria, Heart; Mitochondrial Diseases; Myofibrils; Oxidation-Reduction; Polyenes; Rats; Reactive Oxygen Species; Thiazoles; Ubiquinone

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.

Topics: Biopsy; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Hearing Loss, Sensorineural; Humans; Hyperammonemia; Infant; Leigh Disease; Liver; Liver Failure, Acute; Male; Metabolism, Inborn Errors; Mitochondria, Liver; Mitochondrial Diseases; Oxidative Phosphorylation; Pancreas; Ubiquinone

We report a 9-year-old girl with a mitochondrial cytopathy preceded by steroid-resistant focal segmental glomerulosclerosis (FSGS). The proband presented at the age of 2 years with steroid-resistant nephrotic syndrome caused by FSGS. Her renal function progressively deteriorated and a dilated cardiomyopathy developed at the age of 7 years. A skeletal muscle biopsy showed a combined respiratory chain (RC) defect and a partial deficiency of coenzyme Q(10). A novel mutation in the evolutionary highly conserved region of the mitochondrial tRNA(Tyr) gene was found in homoplasmic state in skeletal muscle, blood, and renal tissue. The mutation was also found in homoplasmic state in her mildly symptomatic mother. No other maternal family members were available for testing. The present case of mitochondrial cytopathy initially presenting with steroid-resistant nephrotic syndrome, unusual biochemical and renal findings associated with a novel tRNA point mutation suggests that steroid-resistant FSGS can predate other features of mitochondrial disease for a prolonged period of time and that the progressive glomerulopathy associated with combined mitochondrial RC defects is genetically heterogeneous.

Topics: Abnormalities, Multiple; Base Sequence; Biopsy; Child; Child, Preschool; Chromatography, High Pressure Liquid; Coenzymes; DNA, Mitochondrial; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunohistochemistry; Kidney; Microscopy, Electron; Mitochondrial Diseases; Molecular Sequence Data; Muscle, Skeletal; Mutation; RNA, Transfer; Sequence Alignment; Sequence Analysis, DNA; Tyrosine; Ubiquinone

Topics: Antioxidants; Clinical Trials as Topic; Coenzymes; Cytoprotection; Humans; Mitochondrial Diseases; Parkinson Disease; Severity of Illness Index; Ubiquinone

The oxidative stress possibly resulting from an inherited respiratory chain (RC) deficiency was investigated in a series of human cultured skin fibroblasts presenting either ubiquinone depletion or isolated defect of the various RC complexes. Taken as an index for superoxide overproduction, a significant induction of superoxide dismutase activity was observed in complex V-deficient fibroblasts harboring the NARP-mutation in the ATPase 6 gene. Superoxide dismutase induction was also noticed, albeit to a lesser extent, in complex II-deficient fibroblasts with a mutation in the nuclear gene encoding the flavoprotein subunit of the succinate dehydrogenase. No sign of oxidative stress could be found in ubiquinone-depleted fibroblasts. In all cases but complex IV-defect, increased oxidative stress was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process associated with all types of RC defect. However, similar to the great variations in oxidative stress associated with the various types of RC defect, we found that apoptotic features differed noticeably between defects. No indication of increased cell death was found in ubiquinone-depleted fibroblasts.

Topics: Aconitate Hydratase; Annexin A5; Antioxidants; Apoptosis; Biopsy; Caspase 3; Caspases; Cells, Cultured; Coenzymes; Cytoprotection; Fibroblasts; Humans; In Situ Nick-End Labeling; Isocitrate Dehydrogenase; Mitochondrial Diseases; Oxidative Stress; Skin; Superoxide Dismutase; Ubiquinone