Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Neurogenetics. 2012 Nov;13(4):375-86. doi: 10.1007/s10048-012-0343-8. Epub 2012 Sep 18.
Mammalian complex V (F1F0-ATP synthase or ATPase) uses the proton gradient to generate ATP during oxidative phosphorylation and requires several helper proteins, including TMEM70, to form the holoenzyme in a stepwise process in which nuclear DNA is combined with mitochondrial DNA-encoded subunits. We report the clinical and molecular findings in three patients presenting lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy. All three showed an isolated defect of fully assembled ATP synthase in association with a "common" (c.317-2A > G) and a new (c.628A > C/p.T210P) variant in TMEM70. Interestingly, one of the patients also showed nitric oxide-responsive pulmonary arterial hypertension, a finding never before associated with TMEM70 deficiency. In addition to widening the clinical and mutational spectrum of defective ATP synthase, our study also suggests that mutant TMEM70 associates in high molecular weight complexes (470-550 kDa) when expressed in Hela cells and exerts a direct action in ATP synthase biogenesis and assembly, mediating the incorporation of F1 moieties.
哺乳动物复合 V（F1F0-ATP 合酶或 ATP 酶）在氧化磷酸化过程中利用质子梯度生成 ATP，需要几种辅助蛋白，包括 TMEM70，以逐步形成全酶，其中核 DNA 与线粒体 DNA 编码的亚基结合。我们报告了 3 名乳酸酸中毒、3-甲基戊二酸尿症和肥厚型心肌病患者的临床和分子发现。所有 3 名患者均表现出完全组装的 ATP 合酶的孤立缺陷，与 TMEM70 中的“常见”（c.317-2A > G）和新（c.628A > C/p.T210P）变异相关。有趣的是，其中一名患者还表现出对一氧化氮有反应的肺动脉高压，这是从未与 TMEM70 缺乏相关的发现。除了扩大有缺陷的 ATP 合酶的临床和突变谱外，我们的研究还表明，突变 TMEM70 在 Hela 细胞中表达时与高分子量复合物（470-550 kDa）相关，并直接作用于 ATP 合酶的生物发生和组装，介导 F1 部分的掺入。
