Miro2 supplies a platform for Parkin translocation to damaged mitochondria

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 

作者机构：State Key Laboratory of Membrane BiologyInstitute of ZoologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Key Laboratory of Genomics and Precision MedicineBeijing Institute of GenomicsUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Department of Foresight and Evaluation ResearchChinese Academy of Science and Technology for DevelopmentBeijing 100038China Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijing 100101China 

出 版 物：《Science Bulletin》 (科学通报（英文版）)

年 卷 期：2019年第64卷第11期

页      面：730-747页

核心收录：

学科分类：07[理学] 08[工学] 

基　　金：supported by the National Natural Science Foundation of China (91754204) the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010107) National Key Research and Development Program of China (2018YFA0108500, 2017YFC1001001) the National NaturalScience Foundation of China (81630078, 31670822, 31401151, 31570816, 81371415) the Natural Science Foundation of Beijing (5181001) CAS Strategic Priority Research Program (XDB14030300) the State Key Laboratory of Membrane Biology the Key Laboratory of Genomic and Precision Medicine 

主　　题：Miro2 Parkin Mitochondria Ca^2+ Mitophagy PINK1 

摘      要：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.