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Mitochondrial E3 ligase MARCH 5 regulates FUNDC 1 to fine‐tune hypoxic mitophagy
Author(s) -
Chen Ziheng,
Liu Lei,
Cheng Qi,
Li Yanjun,
Wu Hao,
Zhang Weilin,
Wang Yueying,
Sehgal Sheikh Arslan,
Siraj Sami,
Wang Xiaohui,
Wang Jun,
Zhu Yushan,
Chen Quan
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643309
Subject(s) - mitophagy , ubiquitin ligase , dna ligase , chemistry , microbiology and biotechnology , biology , biochemistry , ubiquitin , dna , apoptosis , gene , autophagy
Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC 1. It is not clear whether these pathways coordinate to mediate mitophagy in response to stresses, or how mitophagy receptors sense stress signals to activate mitophagy. We find that the mitochondrial E3 ligase MARCH 5, but not Parkin, plays a role in regulating hypoxia‐induced mitophagy by ubiquitylating and degrading FUNDC 1. MARCH 5 directly interacts with FUNDC 1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC 1 by MARCH 5 expression desensitizes mitochondria to hypoxia‐induced mitophagy, whereas knockdown of endogenous MARCH 5 significantly inhibits FUNDC 1 degradation and enhances mitochondrial sensitivity toward mitophagy‐inducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine‐tune mitochondrial quality.