Mitochondria in neuromuscular disorders.
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.
DiMauro
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Department of Neurology, H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia University College of Physicians and Surgeons, 4-420, 630 West 168th Street, New York, NY 10032, USA. sd12@columbia.edu
Bonilla
E
E
Davidson
M
M
Hirano
M
M
Schon
E A
EA
D000818:Animals; D003067:Coenzymes; D030401:Cytochrome-c Oxidase Deficiency; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D017237:Mitochondrial Encephalomyopathies / Q000209:etiology; D017240:Mitochondrial Myopathies / Q000145:classification / Q000209:etiology* / Q000235:genetics; D005810:Multigene Family; D009468:Neuromuscular Diseases / Q000209:etiology* / Q000235:genetics; D017354:Point Mutation; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000235:genetics
D003067:Coenzymes; D004272:DNA, Mitochondrial; D014451:Ubiquinone; D003576:Electron Transport Complex IV; C024989:coenzyme Q10