A mitochondrial SCF‐FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease

Author:

Cao Yu123,Zheng Jing23,Wan Huayun23,Sun Yuqiu234ORCID,Fu Song235,Liu Shanshan23ORCID,He Baiyu236,Cai Gaihong2,Cao Yang2,Huang Huanwei2,Li Qi24,Ma Yan24,Chen She24,Wang Fengchao24,Jiang Hui1234ORCID

Affiliation:

1. College of Life Sciences Beijing Normal University Beijing China

2. National Institute of Biological Sciences Beijing China

3. Beijing Key Laboratory of Cell Biology for Animal Aging Beijing China

4. Tsinghua Institute of Multidisciplinary Biomedical Research Tsinghua University Beijing China

5. Graduate School of Peking Union Medical College Beijing China

6. College of Life Sciences China Agriculture University Beijing China

Abstract

AbstractMitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria‐targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4‐KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer‐membrane protein that forms an SCF‐FBXL4 ubiquitin E3 ligase complex. SCF‐FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF‐FBXL4 assembly and impair substrate degradation. Fbxl4−/− mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4−/− mice. Together, beyond identifying SCF‐FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.

Funder

Beijing Municipal Science and Technology Commission

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

Cited by 41 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3