ubiquinone and Neuromuscular-Diseases

Coenzyme Q

Topics: Biological Availability; Dietary Supplements; Humans; Migraine Disorders; Neoplasms; Neurodegenerative Diseases; Neuromuscular Diseases; Quality of Life; 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

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

This review considers primary mitochondrial diseases affecting the respiratory chain. As diseases due to mitochondrial DNA defects defy traditional anatomical classifications, we have not limited our discussion to neuromuscular disorders, but have extended it to include mitochondrial encephalomyopathies. Primary mitochondrial diseases can be due to mutations in either the nuclear or the mitochondrial genome. Nuclear mutations can affect (i) genes encoding enzymatic or structural mitochondrial proteins; (ii) translocases; (iii) mitochondrial protein importation; and (iv) intergenomic signaling. We review briefly recent molecular data and outstanding questions regarding these mendelian disorders, with special emphasis on cytochrome c oxidase deficiency and coenzyme Q10 deficiency. Mitochondrial DNA mutations fall into three main categories: (i) sporadic rearrangements (deletions/duplications); (ii) maternally inherited rearrangements (duplications); and (iii) maternally inherited point mutations. We summarize the most common clinical presentations and discuss pathogenic mechanisms, which remain largely elusive. Uncertainties about pathogenesis extend to the process of cell death, although excitotoxicity in neurons and apoptosis in muscle seem to have important roles.

Topics: Animals; Coenzymes; Cytochrome-c Oxidase Deficiency; DNA, Mitochondrial; Electron Transport Complex IV; Gene Deletion; Humans; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Multigene Family; Neuromuscular Diseases; Point Mutation; Ubiquinone

Coenzyme Q10 was administered under placebo controlled blinded crossover conditions to six subjects suffering from type 3 3-methylglutaconic aciduria ('optic atrophy plus'), following a report of benefit. Despite attainment of high plasma levels of coenzyme Q10, no clinical benefit was observed and there was no diminution of urinary excretion of 3-methylglutaconic acid.

Topics: Administration, Oral; Adolescent; Adult; Child; Coenzymes; Cross-Over Studies; Female; Glutarates; Humans; Male; Movement Disorders; Neuromuscular Diseases; Optic Atrophy; Single-Blind Method; Treatment Failure; Ubiquinone; Visual Acuity

The aim of this study is to determine whether coenzyme Q (CoQ) muscle concentrations and redox state are associated with pathologic changes in muscle biopsy specimens. Skeletal muscle biopsies were collected (January 2002-February 2004) and underwent pathologic evaluation. Quadriceps specimens (n = 47) were stratified accordingly: Group 1, controls without evidence of pathologic abnormalities; Group 2, type I myofiber predominance; Group 3, type II myofiber atrophy; Group 4, lower motor unit disease; and Group 5, muscular dystrophy. Ubiquinol-10, ubiquinone-10, total coenzyme Q10 (CoQ10), coenzyme Q9 (CoQ9), total CoQ (CoQ9+CoQ10) concentrations were analyzed in biopsy muscle by high-performance liquid chromatography. Ubiquinone-10, total CoQ10, and total CoQ concentrations were significantly decreased in Group 5. Significant positive correlations (r congruent with 0.40) were found between muscle ubiquinone-10, total CoQ10, and total CoQ concentrations vs the percentage of myofibers having subsarcolemmal mitochondrial aggregates. CoQ redox ratio and the fraction CoQ9/total CoQ were negatively correlated with subsarcolemmal mitochondrial aggregates. A significant correlation (r = 0.328) also occurred between ubiquinol-10 concentration and citrate synthase activity. This study suggests that total CoQ concentration provides a new method for estimating mitochondrial activity in biopsy muscle; and that the muscle CoQ test is feasible and potentially useful for diagnosing CoQ deficiency states.

Topics: Adolescent; Biomarkers; Biopsy; Child; Child, Preschool; Female; Humans; Infant; Male; Mitochondria; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Neuromuscular Diseases; Oxidation-Reduction; Ubiquinone

Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo tissue oxygenation and hemodynamics. This method is used to derive relative measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb) accumulation from measurements of optical attenuation at discrete wavelengths. We present the design and validation of a new NIRS oxygenation analyzer for the measurement of muscle oxygenation kinetics. This design optimizes optical sensitivity and detector wavelength flexibility while minimizing component and construction costs. Using in vitro validations, we demonstrate 1) general optical linearity, 2) system stability, and 3) measurement accuracy for isolated Hb. Using in vivo validations, we demonstrate 1) expected oxygenation changes during ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle exercise, 3) a close correlation between changes in oxyhemoglobin and oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by venous occlusion plethysmography, and 4) a minimal contribution from movement artifact on the detected signals. We also demonstrate the ability of this system to detect abnormal patterns of tissue oxygenation in a well-characterized patient with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a valid system design for the precise, accurate, and sensitive detection of changes in bulk skeletal muscle oxygenation, can be constructed economically, and can be used diagnostically in patients with disorders of skeletal muscle energy metabolism.

Topics: Coenzymes; Electronics; Equipment Design; Exercise; Hemoglobins; Humans; Hyperemia; Ischemia; Kinetics; Metabolism, Inborn Errors; Movement; Muscle, Skeletal; Myoglobin; Neuromuscular Diseases; Oxygen; Oxygen Consumption; Plethysmography; Reproducibility of Results; Sensitivity and Specificity; Spectroscopy, Near-Infrared; Ubiquinone

Coenzyme Q10 (CoQ) content was measured in isolated muscle mitochondria from 25 patients with mitochondrial encephalomyopathies (MEM), most of whom had mitochondrial DNA mutations. The CoQ level was significantly lower in MEM patients than in controls. CoQ levels varied widely from patient to patient, especially in those with chronic progressive external ophthalmoplegia including Kearns-Sayre syndrome, which may explain, at least in part, the variable response of patients to CoQ administration.

Topics: Adolescent; Adult; Child; Coenzymes; DNA, Mitochondrial; Female; Humans; Male; Middle Aged; Mitochondria, Muscle; Muscular Diseases; Mutation; Neuromuscular Diseases; Ubiquinone

Many CoQ trials for mitochondrial encephalomyopathy are reported, however, the action of CoQ in the central nervous system is unknown. We administered CoQ to a patient with MELAS, and decreasing CSF lactate and pyruvate levels were revealed. This reduction in CSF lactate and pyruvate may be evidence that CoQ acts directly on the CNS. There have been no other descriptions of evidence of CoQ effective action in the central nervous system, a finding unique to this report.

Topics: Acidosis, Lactic; Adult; Agnosia; Cerebrovascular Disorders; Delirium; Dose-Response Relationship, Drug; Hemianopsia; Humans; Lactates; Lactic Acid; Magnetic Resonance Imaging; Male; Mitochondria, Muscle; Neurologic Examination; Neuromuscular Diseases; Pyruvates; Pyruvic Acid; Syndrome; Ubiquinone

Cytochrome c oxidase (CCO) has been histochemically studied in 250 muscle biopsies from patients with different neuromuscular diseases. The results were compared with those obtained on serial sections stained with Gomori's trichrome and with the methods for NADH tetrazolium reductase, succinate dehydrogenase and lactate dehydrogenase. In 58 selected cases serial sections were also stained with a method demonstrating coenzyme Q (CoQ) activity. Demonstration of structural alterations was as good with CCO as with the methods for other oxidative enzymes: particularly evident were alterations of the distribution of mitochondria, such as core areas in central core and multiminicore diseases. Unstained fibers were observed in mitochondrial myopathies, in Becker, Emery-Dreifuss, limb-girdle, facio-scapulo-humeral muscular dystrophies, muscle infarction, polymyositis, motor neuron diseases and neuropathies. The histochemical method for CoQ showed only low specificity, since partial staining was also present in areas devoid of mitochondria, such as cores. CoQ deficiency was not observed in any of the 19 mitochondrial myopathies examined.

Topics: Biopsy; Electron Transport Complex IV; Histocytochemistry; Humans; Muscles; Neuromuscular Diseases; Ubiquinone

Respiratory chain enzymes were studied in isolated mitochondria of two patients with mitochondrial myopathy. Both patients had been suffering from chronic progressive external ophthalmoplegia and abnormal muscular fatigability since late childhood. One of the patients exhibited the complete triad of symptoms characteristic of Kearns-Sayre syndrome. Venous lactate levels at rest and during minimal exercise were increased in both patients. Histochemical examination of muscle revealed ragged red fibres and intermingled fibres negative for cytochrome c oxidase. Biochemical studies showed decreased activities of complex I and complex IV of the respiratory chain in both patients. Reduced minus oxidized spectra of mitochondrial cytochromes revealed a decreased content of cytochrome aa3 in only one patient, but a normal content in the other. A combined deficiency of complexes I and IV in muscle might either be due to a deficiency of a single subunit common to both complexes or to a coincidental deficiency of both complexes expressed either in the same or in different fibres.

Topics: Adult; Cytochrome-c Oxidase Deficiency; Cytochromes; Female; Humans; Lactates; Middle Aged; Mitochondria, Muscle; Muscles; NAD(P)H Dehydrogenase (Quinone); Neuromuscular Diseases; Pyruvates; Quinone Reductases; Ubiquinone

The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy. The propositus, a 14-year-old female, and her 12-year-old sister had suffered from progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. In the propositus, the state 3 respiratory rate of muscle mitochondria with NADH-linked substrates and with succinate was markedly reduced. The levels of cytochromes a + a3, b, and c + c1 were normal. The activities of complexes I, II, III, and IV of the electron transport chain were normal or increased. By contrast, the activities of complex I-III and of complex II-III, both of which need coenzyme Q10 (CoQ10), were abnormally low. On direct measurement, the mitochondrial CoQ10 content was 3.7% of the mean value observed in 10 controls. Serum and cultured fibroblasts of the propositus had normal CoQ10 contents. In the younger sister, the respiratory activities and CoQ10 level of muscle mitochondria were similar to those observed in the propositus. The findings establish CoQ10 deficiency as a cause of a familial mitochondrial cytopathy and suggest that the disease results from a tissue-specific defect of CoQ10 biosynthesis.

Topics: Adolescent; Child; Coenzyme A; Cytochromes; Electron Transport; Female; Humans; Metabolism, Inborn Errors; Mitochondria, Muscle; Neuromuscular Diseases; Oxygen Consumption; Reference Values; Ubiquinone

Topics: Acidosis, Lactic; Benzoquinones; Brain Diseases, Metabolic; Coenzymes; Female; Humans; Middle Aged; Mitochondria, Muscle; Neuromuscular Diseases; Quinones; Syndrome; Ubiquinone