Wang Jiu-Qiang, Zhu Shu, Wang Yihan, Wang Fengli, An Chaoqiang, Jiang Dongfang, Gao Lijie, Tu Yingfeng, Zhu Xuefei, Wang Yun, Liu Hongmei, Gong Juanjuan, Sun Zhongshuai, Wang Xi, Liu Leimei, Yang Keyan, Guo Caixia, Tang Tie-Shan
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China; Department of Foresight and Evaluation Research, Chinese Academy of Science and Technology for Development, Beijing 100038, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
Sci Bull (Beijing). 2019 Jun 15;64(11):730-747. doi: 10.1016/j.scib.2019.04.033. Epub 2019 May 2.
PINK1/Parkin-mediated mitophagy is an important process in selective removal of damaged mitochondria, in which translocation of Parkin to damaged mitochondria is recognized as an initiation step. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Here we show that Miro2, an outer mitochondrial membrane protein, undergoes demultimerization from a tetramer to a monomer and alteration in mitochondrial localization upon CCCP treatment, suggesting a CCCP-induced realignment of Miro2. The realignment of Miro2 is tightly regulated by PINK1-mediated phosphorylation at Ser325/Ser430 and by Ca binding to EF2 domain, which are both essential for the subsequent Parkin translocation. Interestingly, ablation of Miro2 in mouse causes delayed reticulocyte maturation, lactic acidosis and cardiac disorders. Furthermore, several Miro2 mutations found in the congenital lactic acidosis patients also disable its realignment and Parkin translocation. These findings reveal an important role of Miro2 to mediate Parkin translocation by sensing both depolarization and Ca release from damaged mitochondria to ensure the accuracy of mitophagy.
PINK1/帕金介导的线粒体自噬是选择性清除受损线粒体的重要过程，其中帕金向受损线粒体的转位被认为是起始步骤。目前，帕金如何选择性识别并靶向受损线粒体尚未完全明确。在此我们表明，线粒体外膜蛋白Miro2在CCCP处理后从四聚体解聚为单体，并改变线粒体定位，提示CCCP诱导了Miro2的重新排列。Miro2的重新排列受到PINK1介导的Ser325/Ser430位点磷酸化以及钙与EF2结构域结合的严格调控，这两者对于随后的帕金转位均至关重要。有趣的是，在小鼠中敲除Miro2会导致网织红细胞成熟延迟、乳酸性酸中毒和心脏疾病。此外，在先天性乳酸性酸中毒患者中发现的几个Miro2突变也使其无法重新排列和发生帕金转位。这些发现揭示了Miro2通过感知受损线粒体的去极化和钙释放来介导帕金转位，以确保线粒体自噬准确性的重要作用。
