title: Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy.
abstract: 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 FUNDC1. 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 MARCH5, but not Parkin, plays a role in regulating hypoxia-induced mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia-induced mitophagy, whereas knockdown of endogenousMARCH5significantly inhibits FUNDC1 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.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Ziheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.|Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan.
authors.forename: Sheikh Arslan
authors.initials: SA
authors.lastname: Sehgal
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
authors.forename: Sami
authors.initials: S
authors.lastname: Siraj
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China chenq@ioz.ac.cn.|University of Chinese Academy of Sciences, Beijing, China.|Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Quan
authors.identifier: 0000-0001-7539-8728
authors.initials: Q
authors.lastname: Chen
mesh_terms: D015687:Cell Hypoxia; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D011485:Protein Binding; D055503:Protein Multimerization; D059748:Proteolysis; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C571016:FUNDC1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008239:Lysine
keywords: MARCH5; mitochondrial autophagy; mitophagy receptor; ubiquitylation