The idebenone metabolite QS10 restores electron transfer in complex I and coenzyme Q defects
| Autor: | Francesco Argenton, Valerio Carelli, Marco Schiavone, Maurizio Prato, Valeria Petronilli, Manuel J. Acosta Lopez, Chiara Galber, Paolo Bernardi, Marco Carini, Valentina Giorgio, Tatiana Da Ros, Leonardo Salviati |
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| Přispěvatelé: | Giorgio, Valentina, Schiavone, Marco, Galber, Chiara, Carini, Marco, Da Ros, Tatiana, Petronilli, Valeria, Argenton, Francesco, Carelli, Valerio, Acosta Lopez, Manuel J., Salviati, Leonardo, Prato, Maurizio, Bernardi, Paolo |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antioxidant Embryo Nonmammalian Mitochondrial Diseases Ubiquinone medicine.medical_treatment Mitochondria Liver Pharmacology Biochemistry Complex I Electron transfer Idebenone Respiration Adenosine Triphosphate Animals Antioxidants Ataxia Cell Respiration Cells Cultured Electron Transport Electron Transport Complex I Mice Muscle Weakness Zebrafish chemistry.chemical_compound 0302 clinical medicine Mitochondrial Disease Cultured Nonmammalian Biophysics Cell Biology Mitochondria Liver Embryo medicine.drug Muscle Weakne Cellular respiration Cells 03 medical and health sciences medicine Animal Rotenone 030104 developmental biology Mitochondrial permeability transition pore chemistry Biophysic Coenzyme Q – cytochrome c reductase Adenosine triphosphate 030217 neurology & neurosurgery |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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