ubiquinone and Kidney-Diseases

Mitochondrial nephropathy has a poor prognosis and often progresses to the end-stage renal disease. Renal pathology often is focal segmental glomerulosclerosis (FSGS) and does not respond to steroid therapy or immunosuppressive therapy. Some patients are benefited from the therapy of coenzyme Q10, which affect the synthesis pathway of coenzyme Q10.. Herein, we report 2 cases of children with proteinuria renal disease with ADCK4 mutation.. Proteinuria renal disease with ADCK4 mutation.. Compound heterozygous mutation in ADCK4 gene were detected with next-generation sequencing and confirmed by Sanger sequencing. Both of the patients were given coenzyme Q10 supplementation therapy.. The first patient showed a decreased proteinuria after coenzyme Q10 supplementation therapy, while the other was not improved.. Based on the cases we reported and from the literature, recognition of ADCK4 mutation through early and accurate genetic screening could be helpful in avoiding unnecessary toxicities and in preventing complications arising in mitochondrial nephropathy.

Topics: Child; Dietary Supplements; Female; Humans; Infant; Kidney Diseases; Mutation; Protein Kinases; Proteinuria; Treatment Outcome; Ubiquinone

Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.

Topics: Acute Kidney Injury; Alkyl and Aryl Transferases; Animals; DNA, Mitochondrial; Humans; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria; Mitochondrial Myopathies; Mutation; Oxidative Phosphorylation; Reactive Oxygen Species; Ubiquinone

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

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

Topics: Aging; Antioxidants; Biomarkers; Chromatography, High Pressure Liquid; Drug Monitoring; Electron Transport; Exercise; Heart Failure; Humans; Kidney Diseases; Liver Cirrhosis; Myocardial Ischemia; Myocardial Reperfusion Injury; Oxidative Stress; Reference Values; Specimen Handling; Ubiquinone

Coenzyme Q10 belongs to important antioxidants and it has a key role in the synthesis of adenosinetriphosphate. Its beneficial effect was proved in several diseases, e.g. in mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial cardiomyopathy.. All 15 patients of the studied group (5 with tubulopathy and 10 with chronic tubulointersticial nephritis) received antioxidative therapy for three months (E vitamin, C vitamin, riboflavin) and for the last two months coenzyme Q10 was added. Renal functions, spectrum of lipids, parameters of lipid peroxidation (malondialdehyde), levels of alpha-tocopherol, beta-carotene, coenzyme Q10.. Before the substitutive antioxidative treatment, coenzyme Q10 levels reached in blood 0.11 +/- 0.03 mumol/l and 0.15 +/- 0.04 mumol/l in plasma. These values were well below the reference range (rr) is 0.4 +/- 1.0 mumol/l). After the substitution coenzyme Q10 levels significantly increased (p < 0.001) to the values of 1.66 +/- 0.16 mumol/l in blood and to 1.78 +/- 0.27 mumol/l in plasma. Plasma levels of beta-carotene increased from the markedly subnormal values 0.25 +/- 0.07 mumol/l (rr > 0.8 mumol/l) to 0.56 +/- 0.02 mumol/l (no statistical difference). Plasma levels of alpha-tocopherol remained within the reference range 32.15 +/- 4.73 mumol/l (rr 15-30 mumol/l) and they increased up to the plasma level of 44.83 +/- 5.82 mumol/l during the period of testing. Malondialdehyde levels did not significantly change within the testing period. No changes in renal functions and parameters of lipid metabolism were described. Patients well tolerated the treatment and no adverse effects were seen during the period of observation.. Our results ascertained that levels of antioxidant CoQ10 were lower in patients with nephropathy who underwent conservative treatment with peroral substation. Such deficit can be amended by CoQ10 administration, which could be therefore taken as complementary treatment of nephrology.

Topics: Acidosis, Renal Tubular; Adult; Aged; Aged, 80 and over; Antioxidants; Coenzymes; Female; Humans; Kidney; Kidney Diseases; Male; Malondialdehyde; Middle Aged; Nephritis, Interstitial; Ubiquinone; Vitamins

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.

Topics: Adenosine Triphosphate; Antioxidants; Homeostasis; Humans; Ischemia; Kidney Diseases; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Reactive Oxygen Species; Reperfusion; Reperfusion Injury; Sirtuin 3; Ubiquinone

AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy is a mitochondrial nephropathy caused by mutations in the ADCK4 gene, which disrupt coenzyme Q10 biosynthesis.. We report the case of a 25-year-old female patient with ADCK4-associated glomerulopathy presenting with proteinuria (and with no additional systemic symptoms). A known missense substitution c.737G > A (p.S246N) and a novel frameshift c.577-600del (p.193-200del) mutation were found. We followed the patient for 24 months during supplementation with coenzyme Q10 (20 mg/kg/d - 30 mg/kg/d) and describe the clinical course. In addition, we measured serum and urine coenzyme Q10 levels before and after coenzyme Q10 supplementation and compared them with those of healthy control subjects. The patient's urinary coenzyme Q10 to creatinine ratio was higher than that of healthy controls before coenzyme Q10 supplementation, but decreased consistently with proteinuria after coenzyme Q10 supplementation.. Although the use of urinary coenzyme Q10 as a diagnostic biomarker and predictor of clinical remission in patients with ADCK4-associated glomerulopathy should be confirmed by larger studies, we recommend measuring urinary coenzyme Q10 in patients with isolated proteinuria of unknown cause, since it may provide a diagnostic clue to mitochondrial nephropathy.

Topics: Adult; Biomarkers; Female; Humans; Kidney Diseases; Kidney Glomerulus; Mutation; Predictive Value of Tests; Prognosis; Protein Kinases; 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

Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.. Lupus-prone MRL-. MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .. These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

Topics: Animals; Autoantibodies; Disease Models, Animal; Extracellular Traps; Female; Humans; Interferon Type I; Kidney; Kidney Diseases; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred MRL lpr; Mitochondria; Neutrophils; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; T-Lymphocytes; Ubiquinone

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Antrodia; Arginine; Arterioles; Biological Products; Biomarkers; Blood Pressure; Disease Models, Animal; Hypertension; Inflammation; Kidney; Kidney Diseases; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Oxidative Stress; Rats, Wistar; Ubiquinone

The kidney is one of the most radiosensitive organs in the abdominal cavity and is the dose-limiting structure in cancer patients receiving abdominal or total body irradiation. In the present study, the effect of coenzyme Q10 (CoQ10) on radiation nephropathy was evaluated in rats. A total of 72 rats were equally randomized into 4 groups: Control, CoQ10, irradiation with 10 Gy (RT) + placebo, or RT + CoQ10. The 2 RT groups received single 10 Gy of abdominal irradiation. The 2 CoQ10 groups were supplemented daily with 1 mL of soybean oil containing 10 mg/kg of CoQ10. The RT + placebo and control groups received same dose of soybean oil. After 24 weeks, laboratory and histopathologic findings were compared. The 2 RT groups showed significant increases in blood urea nitrogen (BUN) and creatinine levels and significant pathologic changes such as glomerulosclerosis and tubulointerstitial fibrosis. CoQ10 supplementation resulted in significant reductions of BUN and creatinine levels compared with the RT + placebo group (P < 0.001 and P = 0.038, respectively). CoQ10 treatment significantly attenuated glomerular and tubular changes of irradiated kidney in semiquantitative analysis (P < 0.001 for both). Administration of CoQ10 can alleviate the radiation-induced nephropathy.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Dietary Supplements; Gamma Rays; Kidney; Kidney Diseases; Male; Placebo Effect; Rats; Rats, Sprague-Dawley; Ubiquinone

Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l-NAME hypertensive rats.. Hypertension was induced in rats by l-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured.. Compared to the l-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-α and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent.. The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Cardiovascular Diseases; Hypertension; Kidney Diseases; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar; Ubiquinone; Valsartan; Vitamin D; Vitamins

The nephroprotective effect of coenzyme Q10 and epigallocatechin gallate was investigated in rats with acute renal injury induced by a single nephrotoxic dose of cisplatin. Two days prior to cisplatin administration, epigallocatechin gallate and coenzyme Q10 alone and in four different combinations were given for 6 days. The treatment with antioxidants significantly protected the cisplatin-induced increase in the levels of blood urea nitrogen and serum creatinine. Both the antioxidants alone or in different combinations significantly compensated the increased malondialdehyde and reduced glutathione levels. Moreover, the decrease in the activities of superoxide dismutase, catalase, and glutathione peroxidase and the concentration of selenium, zinc, and copper ions were significantly attenuated in renal tissue. In conclusion, epigallocatechin gallate and coenzyme Q10 are equally effective against cisplatin-induced nephrotoxicity, whereas the intervention by combining these two antioxidants was found to be highly effective at low doses in attenuating oxidative stress in rat kidney.

Topics: Animals; Antineoplastic Agents; Antioxidants; Catechin; Cisplatin; Creatinine; Kidney; Kidney Diseases; Male; Micronutrients; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar; Ubiquinone; Urea

Coenzyme Q10 is a natural antioxidant and scavenger of free radicals. In the present study, we examined the effect of coenzyme Q10 on paraoxonase 1 (PON1) activity, lipid profile, atherogenic indexes and relationship of PON 1 activity by high-density lipoprotein (HDL) and atherogenic indexes in gentamicin (GM)-induced nephrotoxicity rats. Thirty Sprague-Dawley rats were divided into three groups to receive saline; GM, 100 mg/kg/d; and GM plus coenzyme Q10 by 15 mg/kg i.p daily, respectively. After 12 days, animals were anaesthetized, blood samples were also collected before killing to measure the levels of triglyceride (TG), cholesterol (C), low-density lipoprotein (LDL), very low density lipoprotein (VLDL), HDL, atherogenic indexes and the activities of PON1 of all groups were analyzed. Data were analyzed by non-parametric Mann-Whitney test (using SPSS 13 software). Coenzyme Q10 significantly decreased TG, C, LDL, VLDL, atherogenic index, atherogenic coefficient and cardiac risk ratio. HDL level and PON1 activity were significantly increased when treated with coenzyme Q10. Also, the activity of PON 1 correlated positively with HDL and negatively with atherogenic coefficient, cardiac risk ratio 1 and cardiac risk ratio 2. This study showed that coenzyme Q10 exerts beneficial effects on PON1 activity, lipid profile, atherogenic index and correlation of PON 1 activity with HDL and atherogenic index in GM -induced nephrotoxicity rats.

Topics: Animals; Aryldialkylphosphatase; Cholesterol; Cholesterol, LDL; Cholesterol, VLDL; Gentamicins; Kidney Diseases; Lipid Peroxidation; Lipids; Male; Rats; Rats, Sprague-Dawley; Triglycerides; Ubiquinone

The aim of this study was to investigate the toxic impacts of titanium dioxide nanoparticles (TiO₂-NPs) on rat kidneys and the possible prophylactic role of either quercetin or idebenone. TiO₂-NPs were administered orally at either 600 mg or 1 g/kg body weight for 5 consecutive days to evaluate dose-dependent toxicity referred to the OECD guidelines for testing of chemicals. The results showed that administration of either low or high repeated doses of TiO₂-NPs to rats significantly increases serum kideney function biomarkers (urea, creatinine and uric acid) as well as increases in serum glucose and serum immuno- inflammatory biomarkers including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), immunoglobin g (IGg), vascular endothelial growth factor (VEGF, angiogenic factor) and nitric oxide (NO) with a concomitant decrease in renal GSH content versus normal control values. The increase in these biomarkers was more evident in rats intoxicated with high TiO₂-NPs repeated doses. Oral co- administration of either quercetin or idebenone (each 200mg/Kg body weight) daily for three weeks to rats intoxicated by either of the two doses markedly ameliorated TiO₂-NPs induced alteration in the above biomarkers. The prophylactic impacts of both agents on biochemical markers were more pronounced in rats received low TiO₂-NPs repeated doses. The biochemical investigation was supported by histological examination. In conclusion, The data showed the severity in renotoxicity of TiO₂-NPs was dose-dependent and the protective effect of quercetin and idebenone may be related to their antioxidant and anti-inflammatory properties.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Blood Glucose; Creatinine; Cytokines; Dose-Response Relationship, Drug; Inflammation Mediators; Kidney Diseases; Male; Metal Nanoparticles; Particle Size; Quercetin; Rats; Titanium; Ubiquinone; Urea

Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ(10) supplementation and uniquely restores CoQ(9) content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ(9) content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy.

Topics: Albuminuria; Alkyl and Aryl Transferases; Animals; Anticholesteremic Agents; Antioxidants; Energy Metabolism; Female; Hyperglycemia; Kidney; Kidney Diseases; Male; Mice; Mice, Knockout; Mutation, Missense; Oxidative Stress; Probucol; Signal Transduction; 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 Q(10) (CoQ(10)) is a vital lipophilic molecule that transfers electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ(10) has been associated with diverse clinical phenotypes, but, in most patients, the molecular cause is unknown. The first defect in a CoQ(10) biosynthetic gene, COQ2, was identified in a child with encephalomyopathy and nephrotic syndrome and in a younger sibling with only nephropathy. Here, we describe an infant with severe Leigh syndrome, nephrotic syndrome, and CoQ(10) deficiency in muscle and fibroblasts and compound heterozygous mutations in the PDSS2 gene, which encodes a subunit of decaprenyl diphosphate synthase, the first enzyme of the CoQ(10) biosynthetic pathway. Biochemical assays with radiolabeled substrates indicated a severe defect in decaprenyl diphosphate synthase in the patient's fibroblasts. This is the first description of pathogenic mutations in PDSS2 and confirms the molecular and clinical heterogeneity of primary CoQ(10) deficiency.

Topics: Alkyl and Aryl Transferases; Biotin; Carnitine; Case-Control Studies; Cells, Cultured; Coenzymes; Fibroblasts; Humans; Infant; Kidney Diseases; Leigh Disease; Muscle Hypotonia; Mutation; Protein Subunits; Riboflavin; Thiamine; Ubiquinone

Coenzyme Q10 (CoQ10) deficiency has been associated with various clinical phenotypes, including an infantile multisystem disorder. The authors report a 33-month-old boy who presented with corticosteroid-resistant nephrotic syndrome in whom progressive encephalomyopathy later developed. CoQ10 was decreased both in muscle and in fibroblasts. Oral CoQ10 improved the neurologic picture but not the renal dysfunction.

Topics: Atrophy; Brain; Child, Preschool; Coenzymes; Creatinine; Disease Progression; Early Diagnosis; Electron Transport; Female; Humans; Infant; Kidney Diseases; Magnetic Resonance Imaging; Male; Mitochondria; Mitochondrial Encephalomyopathies; Muscle, Skeletal; Recovery of Function; Treatment Outcome; Ubiquinone