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miro2 supplies a platform for Parkin translocation to damaged mitochondria

Science Bulletin 2019年第11期64卷 730-747页

作者： Jiu-Qiang Wang Shu Zhu Yihan Wang Fengli Wang Chaoqiang An Dongfang Jiang Lijie Gao Yingfeng Tu Xuefei Zhu Yun Wang Hongmei Liu Juanjuan Gong Zhongshuai Sun Xi Wang Leimei Liu Keyan Yang Caixia Guo Tie-Shan Tang State Key Laboratory of Membrane Biology Institute of ZoologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Key Laboratory of Genomics and Precision Medicine Beijing Institute of GenomicsUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Department of Foresight and Evaluation Research Chinese Academy of Science and Technology for DevelopmentBeijing 100038China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

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^2+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^2+release from damaged mitochondria to ensure the accuracy of mitophagy.

关键词： miro2 Parkin Mitochondria Ca^2+ Mitophagy PINK1

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