Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Cell Rep. 2018 Jun 5;23(10):2989-3005. doi: 10.1016/j.celrep.2018.05.015.
PINK1 and Parkin mediate mitophagy, the cellular process that clears dysfunctional mitochondria. Mitophagy is regulated by mitochondrial dynamics, but the molecules linking these two processes remain poorly understood. Here, we show that Sam50, the core component of the sorting and assembly machinery (SAM), is a critical regulator of mitochondrial dynamics and PINK1-Parkin-mediated mitophagy. In response to Sam50 depletion, normal tubular mitochondria are first fragmented and subsequently merged into large spheres. Sam50 interacts with PINK1 to facilitate its processing and degradation. Depletion of Sam50 results in PINK1 accumulation, Parkin recruitment, and mitophagy. Interestingly, Sam50 deficiency induces a piecemeal mode of mitophagy that eliminates mitochondria "bit by bit" but spares mtDNA. In C. elegans, the Sam50 homolog gop-3 is required for the maintenance of mitochondrial morphology and mass. Our findings reveal that Sam50 directly links mitochondrial dynamics and mitophagy and that Sam50 depletion induces elimination of mitochondria without affecting mtDNA content.
PINK1 和 Parkin 介导细胞自噬，即清除功能失调线粒体的细胞过程。线粒体自噬受线粒体动力学调节，但将这两个过程联系起来的分子仍知之甚少。在这里，我们表明，分选和装配机制（SAM）的核心组件 Sam50 是线粒体动力学和 PINK1-Parkin 介导的线粒体自噬的关键调节因子。在 Sam50 耗竭的情况下，正常的管状线粒体首先发生片段化，随后融合成大球体。Sam50 与 PINK1 相互作用，促进其加工和降解。Sam50 的耗竭导致 PINK1 积累、Parkin 募集和线粒体自噬。有趣的是，Sam50 缺陷诱导线粒体自噬的分段模式，即线粒体“一点一点”被消除，但 mtDNA 得以保留。在秀丽隐杆线虫中，Sam50 的同源物 gop-3 对于维持线粒体形态和质量是必需的。我们的研究结果表明，Sam50 直接将线粒体动力学和线粒体自噬联系起来，并且 Sam50 耗竭会导致线粒体的消除，而不影响 mtDNA 含量。
