RESUMEN
In addition to their core symptoms, most individuals with autism spectrum disorder (ASD) also experience motor impairments. These impairments are often linked to the cerebellum, which is the focus of the current study. Herein, we utilized a prenatal valproic acid (VPA)-induced rat model of autism and performed RNA sequencing in the cerebellum. Relative to control animals, the VPA-treated offspring demonstrated both abnormal motor coordination and impaired dendritic arborization of Purkinje cells (PCs). Concurrently, we observed a decrease in the cerebellar expression of retinoic acid (RA) synthesis enzymes (RDH10, ALDH1A1), metabolic enzyme (CYP26A2), and lower levels of RA, retinoic acid receptor α (RARα), and Cerebellin2 (CBLN2) in the VPA-treated offspring. However, RA supplementation ameliorated these deficits, restoring motor coordination, normalizing PCs dendritic arborization, and increasing the expression of RA, RARα, and CBLN2. Further, ChIP assays confirmed that RA supplementation enhanced RARα's binding capacity to CBLN2 promoters. Collectively, these findings highlight the therapeutic potential of RA for treating motor incoordination in VPA-induced autism, acting through the RARα-CBLN2 pathway.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Ratas , Animales , Humanos , Ácido Valproico/efectos adversos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Tretinoina/farmacología , Cerebelo/metabolismo , Ataxia/metabolismo , Suplementos Dietéticos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Modelos Animales de EnfermedadRESUMEN
For reasons that remain unclear, endogenous synthesis and tissue levels of coenzyme Q10 (CoQ10) tend to decline with increasing age in at least some tissues. When CoQ10 levels are sufficiently low, this compromises the efficiency of the mitochondrial electron transport chain, such that production of superoxide by site 2 increases and the rate of adenosine triphosphate production declines. Moreover, CoQ10 deficiency can be expected to decrease activities of Sirt1 and Sirt3 deacetylases, believed to be key determinants of health span. Reduction of the cytoplasmic and mitochondrial NAD+/NADH ratio consequent to CoQ10 deficit can be expected to decrease the activity of these deacetylases by lessening availability of their obligate substrate NAD+ The increased oxidant production induced by CoQ10 deficiency can decrease the stability of Sirt1 protein by complementary mechanisms. And CoQ10 deficiency has also been found to lower mRNA expression of Sirt1. An analysis of the roles of Sirt1/Sirt3 in modulation of cellular function helps to rationalise clinical benefits of CoQ10 supplementation reported in heart failure, hypertension, non-alcoholic fatty liver disease, metabolic syndrome and periodontal disease. Hence, correction of CoQ10 deficiency joins a growing list of measures that have potential for amplifying health protective Sirt1/Sirt3 activities.
Asunto(s)
Enfermedades Mitocondriales , Sirtuina 1 , Ataxia/genética , Ataxia/metabolismo , Humanos , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Sirtuina 1/genética , Ubiquinona/deficiencia , Ubiquinona/metabolismo , Ubiquinona/farmacologíaRESUMEN
Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ10 biosynthesis and primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10. There is a need for further studies and well-designed clinical trials, with CoQ10 in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.
Asunto(s)
Envejecimiento/metabolismo , Ataxia , Enfermedades Cardiovasculares , Suplementos Dietéticos , Enfermedades Mitocondriales , Debilidad Muscular , Enfermedades Neurodegenerativas , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Ataxia/tratamiento farmacológico , Ataxia/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Ubiquinona/metabolismo , Ubiquinona/uso terapéuticoRESUMEN
Coenzyme Q10 (CoQ10 ) deficiency is a rare disease characterized by a decreased accumulation of CoQ10 in cell membranes. Considering that CoQ10 synthesis and most of its functions are carried out in mitochondria, CoQ10 deficiency cases are usually considered a mitochondrial disease. A relevant feature of CoQ10 deficiency is that it is the only mitochondrial disease with a successful therapy available, the CoQ10 supplementation. Defects in components of the synthesis machinery caused by mutations in COQ genes generate the primary deficiency of CoQ10 . Mutations in genes that are not directly related to the synthesis machinery cause secondary deficiency. Cases of CoQ10 deficiency without genetic origin are also considered a secondary deficiency. Both types of deficiency can lead to similar clinical manifestations, but the knowledge about primary deficiency is deeper than secondary. However, secondary deficiency cases may be underestimated since many of their clinical manifestations are shared with other pathologies. This review shows the current state of secondary CoQ10 deficiency, which could be even more relevant than primary deficiency for clinical activity. The analysis covers the fundamental features of CoQ10 deficiency, which are necessary to understand the biological and clinical differences between primary and secondary CoQ10 deficiencies. Further, a more in-depth analysis of CoQ10 secondary deficiency was undertaken to consider its origins, introduce a new way of classification, and include aging as a form of secondary deficiency.
Asunto(s)
Envejecimiento/genética , Transferasas Alquil y Aril/genética , Ataxia/genética , GTP Fosfohidrolasas/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Debilidad Muscular/genética , Enfermedad de Niemann-Pick Tipo C/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Envejecimiento/metabolismo , Transferasas Alquil y Aril/metabolismo , Animales , Ataxia/metabolismo , Ataxia/patología , Metabolismo Energético/genética , GTP Fosfohidrolasas/metabolismo , Regulación de la Expresión Génica , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Mutación , Proteína Niemann-Pick C1/genética , Proteína Niemann-Pick C1/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/patología , Transducción de Señal , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Coenzyme Q10 (CoQ, ubiquinone) is a redox-active lipid endogenously synthesized by the cells. The final stage of CoQ biosynthesis is performed at the mitochondrial level by the 'complex Q', where coq2 is responsible for the prenylation of the benzoquinone ring of the molecule. We report that the competitive coq2 inhibitor 4-nitrobenzoate (4-NB) decreased the cellular CoQ content and caused severe impairment of mitochondrial function in the T67 human glioma cell line. In parallel with the reduction in CoQ biosynthesis, the cholesterol level increased, leading to significant perturbation of the plasma membrane physicochemical properties. We show that 4-NB treatment did not significantly affect the cell viability, because of an adaptive metabolic rewiring toward glycolysis. Hypoxia-inducible factor 1α (HIF-1α) stabilization was detected in 4-NB-treated cells, possibly due to the contribution of both reduction in intracellular oxygen tension and ROS overproduction. Exogenous CoQ supplementation partially recovered cholesterol content, HIF-1α degradation, and ROS production, whereas only weakly improved the bioenergetic impairment induced by the CoQ depletion. Our data provide new insights on the effect of CoQ depletion and contribute to shed light on the pathogenic mechanisms of ubiquinone deficiency syndrome.
Asunto(s)
Metabolismo Energético , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ubiquinona/análogos & derivados , Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/metabolismo , Ataxia/metabolismo , Línea Celular Tumoral , Colesterol/metabolismo , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Nitrobenzoatos/farmacología , Estabilidad Proteica/efectos de los fármacos , Ubiquinona/antagonistas & inhibidores , Ubiquinona/biosíntesis , Ubiquinona/deficiencia , Ubiquinona/metabolismoRESUMEN
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+) gradient across lysosome membranes to facilitate the breakdown of cellular waste products. Through the process of ageing, the body becomes deficient in CoQ10, resulting in several systemic manifestations. On a cellular level, one of the consequences of CoQ10 deficiency is apoptosis, which can be visualised in tissues of the central nervous system (CNS). Diseases affecting the retina and brain such as age-related macular degeneration (AMD), glaucoma, Alzheimer's disease (AD) and Parkinson's disease (PD) have shown defects in cellular biochemical reactions attributed to reduced levels of CoQ10. Through further research into the pathogenesis of such conditions, the effects of CoQ10 deficiency can be counteracted through supplementation, early detection and intervention.
Asunto(s)
Ataxia/metabolismo , Encéfalo/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Retina/metabolismo , Ubiquinona/deficiencia , Animales , Ataxia/complicaciones , Ataxia/patología , Encéfalo/patología , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Retina/patología , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMEN
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 ß-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.
Asunto(s)
Ataxia/patología , Carbono/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/patología , Debilidad Muscular/patología , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Sulfuros/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Ataxia/genética , Ataxia/metabolismo , Transporte de Electrón , Complejo I de Transporte de Electrón/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Glutatión/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/genética , Debilidad Muscular/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Transcriptoma , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/farmacología , Vitaminas/farmacologíaRESUMEN
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.
Asunto(s)
Ataxia/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Antioxidantes/metabolismo , Humanos , Inflamación/metabolismo , Ubiquinona/metabolismoRESUMEN
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 Arabidopsis plants. Kidney cells treated with this compound incorporated the B-ring of kaempferol into newly synthesized CoQ, suggesting that the B-ring is metabolized via a mechanism described in plant cells. Kaempferol is a natural flavonoid present in fruits and vegetables and possesses antioxidant, anticancer, and anti-inflammatory therapeutic properties. A better understanding of the role of kaempferol as a CoQ ring precursor makes this bioactive compound a potential candidate for the design of interventions aiming to increase endogenous CoQ biosynthesis and may improve CoQ deficient phenotypes in aging and disease.
Asunto(s)
Antioxidantes/metabolismo , Ataxia/genética , Quempferoles/metabolismo , Enfermedades Mitocondriales/genética , Debilidad Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Ataxia/metabolismo , Ataxia/patología , Células Epiteliales/metabolismo , Flavonoles/metabolismo , Humanos , Riñón/metabolismo , Riñón/patología , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Membranas Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Mutación/genética , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent.
Asunto(s)
Ataxia/genética , Canales de Calcio Tipo N/genética , Corteza Cerebral/metabolismo , Epilepsia Tipo Ausencia/genética , Neuronas/metabolismo , Tálamo/metabolismo , Potenciales de Acción , Factores de Edad , Animales , Ataxia/metabolismo , Ataxia/fisiopatología , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Epilepsia Tipo Ausencia/metabolismo , Epilepsia Tipo Ausencia/fisiopatología , Potenciales Postsinápticos Excitadores/genética , Potenciales Postsinápticos Inhibidores/genética , Potenciales de la Membrana/genética , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Núcleos Talámicos/citología , Tálamo/fisiopatologíaRESUMEN
The aim of this article is to correct a very general error in scientific articles, in textbooks and in the Internet that has become an accepted fact. In this literature, the term "vitamin Eâ³ is used for several similar molecules (both tocopherols and tocotrienols) that have never been shown to have vitamin property, i.e. a protective effect against the human deficiency disease. In fact, the name "vitamin Eâ³ should only be used to define molecules that prevent the human deficiency disease "Ataxia with Vitamin E Deficiency" (AVED). Only one such molecule is known, α-tocopherol. This error may confuse consumers as well as medical doctors, who prescribe vitamin E without realizing that the current use of the name includes molecules of unknown, if not unwanted functions.
Asunto(s)
Antioxidantes/administración & dosificación , Ataxia/dietoterapia , Suplementos Dietéticos , Raquitismo/dietoterapia , Escorbuto/dietoterapia , Deficiencia de Vitamina E/dietoterapia , Ácido Ascórbico/administración & dosificación , Ataxia/metabolismo , Ataxia/fisiopatología , Ataxia/prevención & control , Calcitriol/administración & dosificación , Humanos , Raquitismo/metabolismo , Raquitismo/fisiopatología , Raquitismo/prevención & control , Escorbuto/metabolismo , Escorbuto/fisiopatología , Escorbuto/prevención & control , Estereoisomerismo , Terminología como Asunto , Tocotrienoles/química , Tocotrienoles/clasificación , Vitamina E/administración & dosificación , Deficiencia de Vitamina E/metabolismo , Deficiencia de Vitamina E/fisiopatología , Deficiencia de Vitamina E/prevención & control , alfa-Tocoferol/administración & dosificaciónRESUMEN
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; CoQ10 supplementation in particular has noted cardioprotective benefits. In Saccharomyces cerevisiae, Coq10, a putative START domain protein, is believed to chaperone CoQ to sites where it functions. Yeast coq10 deletion mutants (coq10Δ) synthesize CoQ inefficiently during log phase growth and are respiratory defective and sensitive to oxidative stress. Humans have two orthologs of yeast COQ10, COQ10A and COQ10B Here, we tested the human co-orthologs for their ability to rescue the yeast mutant. We showed that expression of either human ortholog, COQ10A or COQ10B, rescues yeast coq10Δ mutant phenotypes, restoring the function of respiratory-dependent growth on a nonfermentable carbon source and sensitivity to oxidative stress induced by treatment with PUFAs. These effects indicate a strong functional conservation of Coq10 across different organisms. However, neither COQ10A nor COQ10B restored CoQ biosynthesis when expressed in the yeast coq10Δ mutant. The involvement of yeast Coq10 in CoQ biosynthesis may rely on its interactions with another protein, possibly Coq11, which is not found in humans. Coexpression analyses of yeast COQ10 and human COQ10A and COQ10B provide additional insights to functions of these START domain proteins and their potential roles in other biologic pathways.
Asunto(s)
Ataxia/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Antioxidantes/metabolismo , Ataxia/genética , Humanos , Peroxidación de Lípido/fisiología , Espectrometría de Masas , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Debilidad Muscular/genética , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Fosfoproteínas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
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 Q10 (CoQ10) deficiency, suggesting dysregulation of the mevalonate pathway. Secondary CoQ10 deficiency was associated with mitochondrial depolarization and mitophagy activation in FH fibroblasts. Persistent mitophagy altered autophagy flux and induced inflammasome activation accompanied by increased production of cytokines by mutant cells. All the pathological alterations in FH fibroblasts were also reproduced in a human endothelial cell line by LDL-receptor gene silencing. Both increased intracellular cholesterol and mitochondrial dysfunction in FH fibroblasts were partially restored by CoQ10 supplementation. Dysregulated mevalonate pathway in FH, including increased expression of cholesterogenic enzymes and decreased expression of CoQ10 biosynthetic enzymes, was also corrected by CoQ10 treatment. Reduced CoQ10 content and mitochondrial dysfunction may play an important role in the pathophysiology of early atherosclerosis in FH. The diagnosis of CoQ10 deficiency and mitochondrial impairment in FH patients may also be important to establish early treatment with CoQ10.
Asunto(s)
Ataxia/complicaciones , Colesterol/metabolismo , Fibroblastos/patología , Hiperlipoproteinemia Tipo II/complicaciones , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Ubiquinona/deficiencia , Ataxia/metabolismo , Ataxia/patología , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/patología , Lipoproteínas LDL/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Mitofagia , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Especies Reactivas de Oxígeno/metabolismo , Receptores de LDL/metabolismo , Ubiquinona/metabolismoRESUMEN
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Ataxia/tratamiento farmacológico , Sulfuro de Hidrógeno/metabolismo , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Síndrome Nefrótico/tratamiento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Transferasas Alquil y Aril/genética , Animales , Antioxidantes/uso terapéutico , Ataxia/complicaciones , Ataxia/metabolismo , Modelos Animales de Enfermedad , Células HeLa , Humanos , Riñón/metabolismo , Riñón/patología , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/complicaciones , Debilidad Muscular/metabolismo , Síndrome Nefrótico/etiología , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquinona/metabolismo , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
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. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1-COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1-COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway.
Asunto(s)
Ataxia/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Ataxia/tratamiento farmacológico , Ataxia/genética , Genes Fúngicos , Genoma Humano , Humanos , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Modelos Biológicos , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/genética , Mutación , Parabenos/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquinona/biosíntesis , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/uso terapéuticoRESUMEN
BACKGROUND: Coenzyme Q10 (CoQ10) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ10 deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ10 deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD). METHODS: Muscle samples were homogenized whereby 600â¯×g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ10 by stable isotope dilution liquid chromatography tandem mass spectrometry. The experimental group consisted of 156 patients of which 76 had enzymatically confirmed RCDs. To further assist in the diagnosis of CoQ10 deficiency in this cohort, we included sequencing of 18 selected nuclear genes involved with CoQ10 biogenesis in 26 patients with low CoQ10 concentration in muscle samples. RESULTS: Central 95% reference intervals (RI) were established for CoQ10 normalized to citrate synthase (CS) or protein. Nine patients were considered CoQ10 deficient when expressed against CS, while 12 were considered deficient when expressed against protein. In two of these patients the molecular genetic cause could be confirmed, of which one would not have been identified as CoQ10 deficient if expressed only against protein content. CONCLUSION: In this retrospective study, we report a central 95% reference interval for 600â¯×g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ10 quantification as part of a diagnostic approach to study mitochondrial disease as it may complement respiratory chain enzyme assays with the possible identification of patients that may benefit from CoQ10 supplementation. However, the anomaly that only a few patients were identified as CoQ10 deficient against both markers (CS and protein), while the majority of patients where only CoQ10 deficient against one of the markers (and not the other), remains problematic. We therefore conclude from our data that, to prevent possibly not diagnosing a potential CoQ10 deficiency, the expression of CoQ10 levels in muscle on both CS as well as protein content should be considered.
Asunto(s)
Ataxia/diagnóstico , Metabolismo Energético/genética , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Debilidad Muscular/diagnóstico , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Adulto , Ataxia/metabolismo , Ataxia/fisiopatología , Células Cultivadas , Transporte de Electrón/genética , Femenino , Regulación de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/fisiopatología , Debilidad Muscular/metabolismo , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Estudios Retrospectivos , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). In COQ4, COQ7 and COQ9 deficient cell lines, we detected significantly elevated levels of 6-DMQ. This suggests a functional interplay of these proteins. However, additional siRNA studies demonstrated that elevated 6-DMQ levels are not an exclusive marker of the COQ7/COQ9 enzymatic step of CoQ10 biosynthesis but constitute a more general phenomenon that occurs in disorders impairing the function or stability of the CoQ-synthome. To further investigate the interdependence of CoQ10 biosynthesis enzyme expression, we performed immunoblotting in various cell lines with CoQ10 deficiency, indicating that COQ4, COQ7 and COQ9 protein expression levels are highly regulated depending on the underlying defect. Supplementation of cell lines with synthetic CoQ precursor compounds demonstrated beneficial effects of 2,4-dihydroxybenzoic acid in COQ7 and COQ9 deficiency. Moreover, vanillic acid selectively stimulated CoQ10 biosynthesis and improved cell viability in COQ9 deficiency. However, compounds tested in this study failed to rescue COQ4 deficiency.
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Ataxia/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Hidroxibenzoatos/farmacología , Mitocondrias/metabolismo , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Fosforilación Oxidativa , Espectrometría de Masas en Tándem , Ubiquinona/biosíntesis , Ubiquinona/metabolismo , Ácido Vanílico/farmacologíaRESUMEN
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.
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Ataxia/metabolismo , Cerebelo/metabolismo , Enfermedades Mitocondriales/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Anciano , Anciano de 80 o más Años , Ataxia/complicaciones , Ataxia/patología , Estudios de Casos y Controles , Cerebelo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Estrés Oxidativo/fisiología , Ubiquinona/metabolismoRESUMEN
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.
Asunto(s)
Ataxia/metabolismo , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/biosíntesis , Ubiquinona/deficiencia , Adenosina Trifosfato/agonistas , Adenosina Trifosfato/biosíntesis , Adenosina Trifosfato/deficiencia , Animales , Ataxia/tratamiento farmacológico , Ataxia/genética , Ataxia/fisiopatología , Transporte de Electrón , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Humanos , Mitocondrias/genética , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/fisiopatología , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Mutación , Multimerización de Proteína , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/uso terapéuticoRESUMEN
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.