Mattiazzi Marina, Vijayvergiya Chetan, Gajewski Carl D, DeVivo Darryl C, Lenaz Giorgio, Wiedmann Martin, Manfredi Giovanni
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA.
Hum Mol Genet. 2004 Apr 15;13(8):869-79. doi: 10.1093/hmg/ddh103. Epub 2004 Mar 3.
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.
线粒体DNA中的T8993G点突变导致线粒体F1F0 - ATP酶的MTATP6亚基中亮氨酸156被精氨酸取代。T8993G突变在两种线粒体疾病中导致氧化磷酸化（OXPHOS）受损，这两种疾病分别是神经病变、共济失调和色素性视网膜炎（NARP）以及母系遗传的 Leigh 综合征（MILS）。在一些研究中曾报道，T8993G突变导致组装好的F1F0 - ATP酶缺失。其他研究报道该突变导致质子通过F0的过程受损。此外，研究表明NARP患者的成纤维细胞有发生凋亡性细胞死亡的倾向，这可能是自由基产生增加的结果。在此，我们表明T8993G突变抑制氧化磷酸化并导致自由基产生增加。我们认为自由基介导的对OXPHOS的抑制作用导致了ATP合成的丧失。重要的是，我们表明抗氧化剂可恢复携带T8993G突变的细胞的呼吸并部分挽救ATP合成。我们的结果表明自由基可能在NARP/MILS的发病机制中起重要作用，并且这可以通过抗氧化剂来预防。抗氧化剂在培养的NARP/MILS细胞中的有效性表明它们可能在NARP患者的治疗中具有潜在的有益作用。
