Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine‐tune hypoxic mitophagy. (19th January 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO reports. Volume 18:Number 3(2017)
• Page Start: 495
• Page End: 509
• Publication Date: 2017-01-19
• Subjects: MARCH5 -- mitochondrial autophagy -- mitophagy receptor -- ubiquitylation; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201643309
• Languages: English
• ISSNs: 1469-221X

Abstract

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 endogenous MARCH5 significantly 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. Synopsis: The E3 ubiquitin ligase MARCH5 targets the mitophagy receptor FUNDC1 for degradation, which desensitizes mitochondrial clearance and fine‐tunes mitophagy under hypoxic stress. FUNDC1 is rapidly ubiquitylated and degraded before hypoxia‐induced mitophagy can occur. MARCH5 ubiquitylates FUNDC1 at lysine 119 for its proteasomal degradation. Hypoxic stress reduces MARCH5 oligomerization and enhances its interaction with FUNDC1. The MARCH5/FUNDC1 axis fine‐tunes hypoxia‐induced mitophagy. Abstract : The E3 ubiquitin ligase MARCH5 targets the mitophagy receptor FUNDC1 for degradation, which desensitizes mitochondrial clearance and fine‐tunes mitophagy under hypoxic stress.