The pathogenic m.8993 T > G mutation in mitochondrial ATP6 gene prevents proton release from the subunit c-ring rotor of ATP synthase.
The pathogenic m.8993 T > G mutation in mitochondrial ATP6 gene prevents proton release from the subunit c-ring rotor of ATP synthase.
复制标题
线粒体 ATP6 基因中的致病性 m.8993 T→→G 突变阻止质子从 ATP 合酶亚基 C 环转子中释放。
DOI：
10.1093/hmg/ddab043
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发表时间：
2021
影响因子：
3.5
通讯作者：
Tribouillard-Tanvier,Déborah
中科院分区：
文献类型：
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作者：
Su,Xin;Dautant,Alain;Rak,Malgorzata;Godard,François;Ezkurdia,Nahia;Bouhier,Marine;Bietenhader,Maïlis;Mueller,DavidM;Kucharczyk,Roza;diRago,Jean-Paul;Tribouillard-Tanvier,Déborah
人类ATP合成酶是由18种不同类型的29个亚基组成的集合，其中只有两个亚基(Aa8)在线粒体基因组中编码。Subunita与Fc亚基的低聚环(c环)一起形成质子通道，负责质子通过线粒体内膜的运输，耦合c环的旋转和ATP的合成。神经肌肉疾病与编码亚单位ATP6基因的许多突变有关。最常见的是m.8993-T >； G，导致一个严格保守的亮氨酸残基被精氨酸(AL156R)取代。我们之前的研究表明，等量突变(AL173R)显著影响酿酒酵母的呼吸生长，并导致线粒体ATP合成速率下降90%。在这里，我们从aL173R菌株中分离出了显示出呼吸生长改善的逆转株。在密码子173(aL173M、aL173S、aL173K和aL173W)有4个第一位点回复，在另一个密码子(aR169M、aR169S、aA170P、aA170G和aI216S)有5个第二位点回复。根据酵母ATP合成酶的原子结构和突变菌株的生化特性，我们认为L173R突变是导致不利的静电相互作用的原因，这种相互作用阻止质子从C环释放到质子从C环向线粒体基质移动的通道。这些结果提供了进一步的证据，表明酵母L173(因此人类L156)优化了质子从ATP合成酶中的退出，但尽管它在进化上是严格保守的，但它并不是必需的。
The human ATP synthase is an assembly of 29 subunits of 18 different types, of which only two (aand8) are encoded in the mitochondrial genome. Subunita,together with an oligomeric ring ofc-subunit (c-ring), forms the proton pathway responsible for the transport of protons through the mitochondrial inner membrane, coupled to rotation of thec-ring and ATP synthesis. Neuromuscular diseases have been associated to a number of mutations in the gene encoding subunita,ATP6. The most common, m.8993 T > G, leads to replacement of a strictly conserved leucine residue with arginine (aL156R). We previously showed that the equivalent mutation (aL173R) dramatically compromises respiratory growth ofSaccharomyces cerevisiaeand causes a 90% drop in the rate of mitochondrial ATP synthesis. Here, we isolated revertants from theaL173R strain that show improved respiratory growth. Four first-site reversions at codon 173 (aL173M,aL173S,aL173K andaL173W) and five second-site reversions at another codon (aR169M,aR169S,aA170P,aA170G andaI216S) were identified. Based on the atomic structures of yeast ATP synthase and the biochemical properties of the revertant strains, we propose that theaL173R mutation is responsible for unfavorable electrostatic interactions that prevent the release of protons from thec-ring into a channel from which protons move from thec-ring to the mitochondrial matrix. The results provide further evidence that yeastaL173(and thus humanaL156) optimizes the exit of protons from ATP synthase, but is not essential despite its strict evolutionary conservation.