Paradoxical Mitophagy Regulation by PINK1 and TUFm

Jingjing Lin, Kai Chen, Wenfeng Chen, Yizhou Yao, Shiwei Ni, Meina Ye, Guifeng Zhuang, Minhuang Hu, Jun Gao, Caixi Gao, Yan Liu, Mingjuan Yang, Zhenkun Zhang, Xiaohui Zhang, Jiexiang Huang, Fei Chen, Ling Sun, Xi Zhang, Suhong Yu, Yuling ChenYating Jiang, Shujuan Wang, Xiaozhen Yang, Ke Liu, Hai Meng Zhou, Zhiliang Ji, Haiteng Deng, M. Emdadul Haque, Junxiang Li, Li Zhi Mi, Yuexi Li, Yufeng Yang

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)607-620.e12
JournalMolecular Cell
Volume80
Issue number4
DOIs
Publication statusPublished - Nov 19 2020

Keywords

  • Atg5-Atg12
  • PINK1
  • Parkin
  • Parkinson's disease
  • TUFm
  • homeostatic control
  • mitophagy
  • paradoxical signaling
  • robustness
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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