Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway
Abstract
The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2 −/− mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia–reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Qi-Qiang Guo
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Shan-Shan Wang
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Xiao-You Jiang
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Xiao-Chen Xie
Department of Endocrinology and Metabolism, Institute of Endocrinology, National Health Commission of the People’s Republic of China, Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University
Yu Zou
Jing-Wei Liu
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Yang Guo
Department of Materials Science and Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon 999077, Hong Kong SAR, China
Yu-Han Li
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Xi-Yan Liu
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Shuang Hao
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Xin-Yue Zhang
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Xiao-Xu Wu
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Song-Ming Lu
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Hong-De Xu
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Wen-Dong Guo
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Yan-Ling Feng
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Chuan-Gui Wang
The Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology
Sheng-Ping Zhang
The Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology
Jia-Bin Li
Chen Liu
Xiao-Yu Song
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Toren Finkel
Liu Cao
Computational Biology Department, School of Computer Science