UBQLN2 and HSP70 participate in Parkin‐mediated mitophagy by facilitating outer mitochondrial membrane rupture

Author:

Ma Qilian12,Xin Jiaqi1,Peng Qiang1,Li Ningning1,Sun Shan13,Hou Hongyu1,Ma Guoqiang1ORCID,Wang Nana1,Zhang Li4,Tam Kin Yip3ORCID,Dussmann Heiko2ORCID,Prehn Jochen HM2ORCID,Wang Hongfeng1ORCID,Ying Zheng1ORCID

Affiliation:

1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow University Suzhou China

2. Department of Physiology & Medical Physics and FUTURE‐NEURO Research Centre Royal College of Surgeons in Ireland Dublin Ireland

3. Faculty of Health Sciences University of Macau Macau China

4. Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine Jiangsu Institute of Nuclear Medicine Wuxi China

Abstract

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging‐related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin‐proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2‐mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin‐dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly‐ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS‐driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin‐mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2‐mediated neurodegeneration.

Funder

Erasmus+

National Natural Science Foundation of China

Priority Academic Program Development of Jiangsu Higher Education Institutions

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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