Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery
Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery
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DOI：
10.1038/s41467-019-12382-4
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发表时间：
2019-09-27
影响因子：
16.6
通讯作者：
Kittler, Josef T.
中科院分区：
文献类型：
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作者：
Modi, Souvik;Lopez-Domenech, Guillermo;Kittler, Josef T.
线粒体 Rho (Miro) GTP 酶定位于线粒体外膜，是调节线粒体运输至特定亚细胞位置的重要机制。然而，它们的线粒体亚定位以及与其他关键线粒体复合物的关系仍然知之甚少。在这里，使用超分辨率荧光显微镜，我们报告 Miro 蛋白沿着线粒体外膜形成纳米大小的簇，与线粒体接触位点和嵴组织系统 (MICOS) 相关。使用敲除小鼠胚胎成纤维细胞，我们发现 Miro1 和 Miro2 是正常线粒体嵴结构和内质网-线粒体接触位点 (ERMCS) 所必需的。此外，我们还发现 Miro 将 MICOS 与 TRAK 运动蛋白接头偶联，以确保两个线粒体膜的协同运输以及嵴在线粒体膜上的正确分布。 Miro 纳米级组织、与 MICOS 复合物的关联以及 EMCS 的调节揭示了 Miro GTPases 对线粒体功能的新控制水平。
Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality.