Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
J Cell Biol. 2021 May 3;220(5). doi: 10.1083/jcb.202010004.
Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson's disease pathogenesis.
线粒体被排除在分泌途径之外，其脂质供应依赖于内质网上的脂质转运蛋白，因为大多数脂质都是在内质网上合成的。在酵母中，外膜 GTPase Gem1 是 ERMES 的辅助因子，后者是一种内质网-线粒体连接复合物，包含脂质转运结构域，并与 Vps13 部分冗余地参与两个细胞器之间的脂质转移。在后生动物中，虽然存在 VPS13，但不存在 ERMES，Gem1 的同源物 Miro 与线粒体动力学有关，但与脂质转运无关。在这里，我们表明 Miro（包括其富含过氧化物酶体的剪接变体）募集脂质转运蛋白 VPS13D，后者反过来以 VAP 依赖的方式与内质网结合，因此可以在 ER 和线粒体之间提供脂质通道。这些发现揭示了酵母和高等真核生物中 Gem1/Miro 功能之间的一个缺失环节，在这些生物中，Miro 是 Parkin 的底物，这可能对帕金森病的发病机制有潜在影响。
