Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1
Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1
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DOI：
10.1038/s41586-019-1372-3
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发表时间：
2019-07-18
期刊：
影响因子：
64.8
通讯作者：
Daumke, Oliver
中科院分区：
文献类型：
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作者：
Faelber, Katja;Dietrich, Lea;Daumke, Oliver
平衡的融合和分裂是线粒体正常功能和生理学的关键（1，2）。线粒体内膜的重塑由真菌中的动力蛋白样蛋白线粒体基因组维持1（Mgm 1）或动物中的相关蛋白视神经萎缩1（OPA 1）介导（3 - 5）。Mgm1是酵母中线粒体DNA保存所必需的（6），而人类OPA1基因突变是常染色体显性视神经萎缩的常见原因，这是一种影响视神经的遗传性疾病（7，8）。Mgm1和OPA1以膜完整的长形式和可溶于膜间隙的短形式存在于线粒体中。表达Mgm的温度敏感突变体的酵母菌株（19，10）或缺乏OPA 1的哺乳动物细胞显示片段化的线粒体（11，12），这表明Mgm 1和OPA 1在内膜融合中具有重要作用。一致地，只有线粒体外膜-而不是内膜-在功能性Mgm 1缺失的情况下融合（13）。Mgm 1和OPA 1也被证明可以维持适当的嵴结构（10，14）;例如，OPA 1通过收紧嵴连接来防止促凋亡因子的释放（15）。最后，OPA1的短形式定位于线粒体收缩部位，在那里它可能促进线粒体分裂（16）。Mgm 1和OPA 1如何在膜融合、断裂和嵴组织中发挥其不同的功能目前尚不清楚。在这里，我们提出的晶体和电子cryo-tomography结构的Mgm1从嗜热毛壳。Mgm1由一个GT3（G）结构域、一个束信号元件结构域、一个茎和一个含有膜结合位点的桨状结构域组成。生物化学和细胞为基础的实验表明，Mgm1茎介导的弯曲四聚体组装成螺旋丝。MgM1装饰的脂质管和荧光显微镜实验重建膜管的电子冷冻断层扫描研究表明，四聚体组装积极或消极的弯曲膜。我们的研究结果传达了Mgm1和OPA1细丝如何动态重塑线粒体内膜。
Balanced fusion and fission are key for the proper function and physiology of mitochondria(1,2). 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(3-5). Mgm1 is required for the preservation of mitochondrial DNA in yeast(6), 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(7,8). 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 Mgm(19,10) or mammalian cells that lack OPA1 display fragmented mitochondria(11,12), 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(13). Mgm1 and OPA1 have also been shown to maintain proper cristae architecture(10,14); for example, OPA1 prevents the release of proapoptotic factors by tightening crista junctions(15). Finally, the short form of OPA1 localizes to mitochondrial constriction sites, where it presumably promotes mitochondrial fission(16). 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.