The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants Journal Article
| Authors: | Mattiazzi, M.; Vijayvergiya, C.; Gajewski, C. D.; DeVivo, D. C.; Lenaz, G.; Wiedmann, M.; Manfredi, G. |
| Article Title: | The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants |
| Abstract: | A T8993G point mutation in the mtDNA results in a Leu156Arg substitution in the MTATP6 subunit of the mitochondrial F1F0-ATPase. The T8993G mutation causes impaired oxidative phosphorylation (OXPHOS) in two mitochondrial disorders, NARP (neuropathy, ataxia and retinitis pigmentosa) and MILS (maternally inherited Leigh's syndrome). It has been reported, in some studies, that the T8993G mutation results in loss of assembled F1F0-ATPase. Others reported that the mutation causes impairment of proton flow through F0. In addition, it was shown that fibroblasts from NARP subjects have a tendency to undergo apoptotic cell death, perhaps as a result of increased free radical production. Here, we show that the T8993G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. We suggest that free radical-mediated inhibition of OXPHOS contributes to the loss of ATP synthesis. Importantly, we show that antioxidants restore respiration and partially rescue ATP synthesis in cells harboring the T8993G mutation. Our results indicate that free radicals might play an important role in the pathogenesis of NARP/MILS and that this can be prevented by antioxidants. The effectiveness of antioxidant agents in cultured NARP/MILS cells suggests that they might have a potential beneficial role in the treatment of patients with NARP. © Oxford University Press 2004; all rights reserved. |
| Keywords: | controlled study; human cell; mutation; pathogenesis; drug efficacy; nonhuman; animal cell; neuropathy; oxygen; lipid; cell culture; guanine; fibroblast; reactive oxygen species; reactive oxygen metabolite; antioxidant; antioxidants; adenosine triphosphate; point mutation; dna, mitochondrial; lipid peroxidation; ataxia; oxidative phosphorylation; synthesis; hydrogen-ion concentration; mitochondrial dna; copper zinc superoxide dismutase; retinitis pigmentosa; mitochondrial respiration; thymine; cytochrome c oxidase; respiratory chain; manganese superoxide dismutase; acetylcysteine; free radical; leigh disease; oligomycin; rotenone; cell respiration; ubidecarenone; humans; human; priority journal; article; carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone; dihydrolipoate; lipid hydroperoxide; cybrid; extrachromosomal inheritance; genetic load; proton-translocating atpases |
| Journal Title: | Human Molecular Genetics |
| Volume: | 13 |
| Issue: | 8 |
| ISSN: | 0964-6906 |
| Publisher: | Oxford University Press |
| Date Published: | 2004-04-15 |
| Start Page: | 869 |
| End Page: | 879 |
| Language: | English |
| DOI: | 10.1093/hmg/ddh103 |
| PROVIDER: | scopus |
| PUBMED: | 14998933 |
| DOI/URL: | |
| Notes: | Hum. Mol. Genet. -- Cited By (since 1996):99 -- Export Date: 16 June 2014 -- CODEN: HMGEE -- Source: Scopus |
