@article{9142cefa70994d62b7f3365634ae2e34,
title = "Paradoxical Mitophagy Regulation by PINK1 and TUFm",
abstract = "Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.",
keywords = "Atg5-Atg12, PINK1, Parkin, Parkinson's disease, TUFm, homeostatic control, mitophagy, paradoxical signaling, robustness, ubiquitin",
author = "Jingjing Lin and Kai Chen and Wenfeng Chen and Yizhou Yao and Shiwei Ni and Meina Ye and Guifeng Zhuang and Minhuang Hu and Jun Gao and Caixi Gao and Yan Liu and Mingjuan Yang and Zhenkun Zhang and Xiaohui Zhang and Jiexiang Huang and Fei Chen and Ling Sun and Xi Zhang and Suhong Yu and Yuling Chen and Yating Jiang and Shujuan Wang and Xiaozhen Yang and Ke Liu and Zhou, {Hai Meng} and Zhiliang Ji and Haiteng Deng and Haque, {M. Emdadul} and Junxiang Li and Mi, {Li Zhi} and Yuexi Li and Yufeng Yang",
note = "Funding Information: We thank Bingwei Lu, Yingshi Ouyang, Dahua Chen, and Xun Huang for critical comments and helpful advice; Bingwei Lu, Eric Baehrecke, and Jongkyeong Chung for sharing key fly strains; Wei Wu at the Core Facility of Drosophila Resource and Technology, SIBCB, CAS for providing fly services and fly stocks; the Tsinghua Drosophila Resource Center for providing fly stocks; Atsushi Miyawaki for the mito-mKeima plasmid; and Richard Youle for plasmids related to the FKBP-rapalog-FRB heterodimerization technique. We thank Guangzhou Sagene Biotech for graphics design. This work was supported in part by the National Natural Science Foundation of China ( 31070877 , 31071296 , and 31970461 ); the Open Research Fund of State Key Laboratory of Cellular Stress Biology , Xiamen University ( SKLCSB2020KF001 ); a Province Min-River scholar grant ( XRC-0947 ); in part by the Key Laboratory of Primate Neurobiology , Institute of Neuroscience , Shanghai Institutes for Biological Sciences , Chinese Academy of Sciences ; startup funds from Fuzhou University ( XRC-1463 and XRC-1465 ); Fujian Natural Science Foundation ( 2016J01158 and 2017J0106 ); Education and Scientific Research Projects for Young Teachers in Fujian Province ( JAT160071 and JT180036 ); and a United Arab Emirates University research grant ( 31M090 ). Funding Information: We thank Bingwei Lu, Yingshi Ouyang, Dahua Chen, and Xun Huang for critical comments and helpful advice; Bingwei Lu, Eric Baehrecke, and Jongkyeong Chung for sharing key fly strains; Wei Wu at the Core Facility of Drosophila Resource and Technology, SIBCB, CAS for providing fly services and fly stocks; the Tsinghua Drosophila Resource Center for providing fly stocks; Atsushi Miyawaki for the mito-mKeima plasmid; and Richard Youle for plasmids related to the FKBP-rapalog-FRB heterodimerization technique. We thank Guangzhou Sagene Biotech for graphics design. This work was supported in part by the National Natural Science Foundation of China (31070877, 31071296, and 31970461); the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2020KF001); a Province Min-River scholar grant (XRC-0947); in part by the Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; startup funds from Fuzhou University (XRC-1463 and XRC-1465); Fujian Natural Science Foundation (2016J01158 and 2017J0106); Education and Scientific Research Projects for Young Teachers in Fujian Province (JAT160071 and JT180036); and a United Arab Emirates University research grant (31M090). Y. Yang. conceived the project and supervised the experiments. J. Lin, G.Z. Y. Liu, L.S. M. Yang, F.C. M.E.H. K.C. and Xiaohui Zhang. performed fly genetics, immunohistochemistry, and imaging experiments. Xi Zhang, J. Lin, G.Z. and K.C. performed p-element constructions and microinjections. K.C. J. Lin, M. Ye, Y. Yao, M.H. J.H. H.-M.Z. J.G. C.G. Y.J. S.W. and L.-Z.M. performed western blotting and biochemistry experiments. W.C. K.C. Z.Z. M.Y. Y. Yao, M. Ye, M.H. J.G. and C.G. performed human cells studies. Y. Yao, M.H. J.G. J. Li, and Y. Li performed FACS analyses. S.N. X.Y. K.L. and Z.J. performed mathematical modeling. K.C. J. Lin, W.C. Y. Yao, Y. Li, and Y. Yang wrote the manuscript with contributions from the other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = nov,
day = "19",
doi = "10.1016/j.molcel.2020.10.007",
language = "English",
volume = "80",
pages = "607--620.e12",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}