Paradoxical Mitophagy Regulation by PINK1 and TUFm

• Published in: Molecular cell 2020-11, Vol.80 (4), p.607-620.e12
• Main Authors: Lin, Jingjing, Chen, Kai, Chen, Wenfeng, Yao, Yizhou, Ni, Shiwei, Ye, Meina, Zhuang, Guifeng, Hu, Minhuang, Gao, Jun, Gao, Caixi, Liu, Yan, Yang, Mingjuan, Zhang, Zhenkun, Zhang, Xiaohui, Huang, Jiexiang, Chen, Fei, Sun, Ling, Zhang, Xi, Yu, Suhong, Chen, Yuling, Jiang, Yating, Wang, Shujuan, Yang, Xiaozhen, Liu, Ke, Zhou, Hai-Meng, Ji, Zhiliang, Deng, Haiteng, Haque, M. Emdadul, Li, Junxiang, Mi, Li-Zhi, Li, Yuexi, Yang, Yufeng
• Format: Article
• Language: English
• Subjects: Animals; Atg5-Atg12; Cytosol - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Female; HeLa Cells; homeostatic control; Humans; Male; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitophagy; paradoxical signaling; Parkin; Parkinson’s disease; Peptide Elongation Factor Tu - genetics; Peptide Elongation Factor Tu - metabolism; Phosphorylation; PINK1; Protein Interaction Domains and Motifs; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Transport; robustness; TUFm; ubiquitin; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.10.007

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. [Display omitted] •Conserved homeostatic mitophagy regulation involving PINK1/TUFm is disclosed•PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222•PINK1 modulates distribution of mitochondrion-cytosol dual-localized TUFm•Self-antagonizing PINK1/TUFm enhances the robustness of mitophagy regulation Lin et al. uncover fundamental mitophagy homeostatic regulation involving PINK1 and its new kinase substrate TUFm. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. The self-antagonizing feature of PINK1/TUFm is essential for the robustness of mitophagy regulation. These findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.