Crystallography, Max-Delbrück-Centrum for Molecular Medicine, Berlin, Germany.
Department of Structural Biology, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
Nature. 2019 Jul;571(7765):429-433. doi: 10.1038/s41586-019-1372-3. Epub 2019 Jul 10.
Balanced fusion and fission are key for the proper function and physiology of mitochondria. Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals. Mgm1 is required for the preservation of mitochondrial DNA in yeast, whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy-a genetic disorder that affects the optic nerve. Mgm1 and OPA1 are present in mitochondria as a membrane-integral long form and a short form that is soluble in the intermembrane space. Yeast strains that express temperature-sensitive mutants of Mgm1 or mammalian cells that lack OPA1 display fragmented mitochondria, which suggests that Mgm1 and OPA1 have an important role in inner-membrane fusion. Consistently, only the mitochondrial outer membrane-not the inner membrane-fuses in the absence of functional Mgm1. Mgm1 and OPA1 have also been shown to maintain proper cristae architecture; for example, OPA1 prevents the release of pro-apoptotic factors by tightening crista junctions. Finally, the short form of OPA1 localizes to mitochondrial constriction sites, where it presumably promotes mitochondrial fission. How Mgm1 and OPA1 perform their diverse functions in membrane fusion, scission and cristae organization is at present unknown. Here we present crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum. Mgm1 consists of a GTPase (G) domain, a bundle signalling element domain, a stalk, and a paddle domain that contains a membrane-binding site. Biochemical and cell-based experiments demonstrate that the Mgm1 stalk mediates the assembly of bent tetramers into helical filaments. Electron cryo-tomography studies of Mgm1-decorated lipid tubes and fluorescence microscopy experiments on reconstituted membrane tubes indicate how the tetramers assemble on positively or negatively curved membranes. Our findings convey how Mgm1 and OPA1 filaments dynamically remodel the mitochondrial inner membrane.
线粒体的正常功能和生理学需要平衡的融合和裂变。真菌中的 dynamin 样蛋白线粒体基因组维持 1 蛋白（Mgm1）或动物中的相关蛋白视神经萎缩 1 蛋白（OPA1）介导了线粒体内膜的重塑。Mgm1 对于酵母中线粒体 DNA 的保存是必需的，而人类 OPA1 基因突变是常染色体显性视神经萎缩的一个常见原因——一种影响视神经的遗传疾病。Mgm1 和 OPA1 在线粒体中以膜整合的长形式和可溶在膜间隙中的短形式存在。表达 Mgm1 温度敏感突变体的酵母菌株或缺乏 OPA1 的哺乳动物细胞显示出碎片化的线粒体，这表明 Mgm1 和 OPA1 在内膜融合中具有重要作用。一致地，只有线粒体的外膜——而不是内膜——在缺乏功能性 Mgm1 的情况下融合。Mgm1 和 OPA1 也被证明可以维持嵴结构的正确形态；例如，OPA1 通过收紧嵴连接来防止促凋亡因子的释放。最后，OPA1 的短形式定位于线粒体收缩部位，推测它在此处促进线粒体裂变。目前尚不清楚 Mgm1 和 OPA1 如何在膜融合、分裂和嵴组织中发挥其多样化的功能。在这里，我们展示了嗜热毛壳菌（Chaetomium thermophilum）的 Mgm1 的晶体和电子低温断层扫描结构。Mgm1 由 GTPase（G）结构域、束信号元件结构域、柄部和含有膜结合位点的桨叶结构域组成。生化和基于细胞的实验表明，Mgm1 柄部介导弯曲四聚体组装成螺旋丝。Mgm1 修饰的脂质管的电子低温断层扫描研究和重组膜管的荧光显微镜实验表明了四聚体如何在正或负曲率的膜上组装。我们的研究结果传达了 Mgm1 和 OPA1 丝动态重塑线粒体内膜的方式。
