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  3. Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway

Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway

  • Proc Natl Acad Sci U S A. 2025 Oct 7;122(40):e2502841122. doi: 10.1073/pnas.2502841122.
Qi-Qiang Guo # 1 2,  Shan-Shan Wang # 1 2,  Xiao-You Jiang # 1 2,  Xiao-Chen Xie # 3,  Yu Zou 1 2,  Jing-Wei Liu 1 2,  Yang Guo 1 2,  Yu-Han Li 1 2,  Xi-Yan Liu 1 2,  Shuang Hao 1 2,  Xin-Yue Zhang 1 2,  Xiao-Xu Wu 1 2,  Song-Ming Lu 1 2,  Hong-De Xu 1 2,  Wen-Dong Guo 1 2,  Yan-Ling Feng 1 2,  Chuan-Gui Wang 4,  Sheng-Ping Zhang 4,  Jia-Bin Li 5,  Chen Liu 5,  Xiao-Yu Song 1 2,  Toren Finkel 6,  Liu Cao 1 2
Affiliations

Affiliations

  • 1 The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning, China.
  • 2 Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang 110122, Liaoning, China.
  • 3 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, Shenyang 110122, Liaoning, China.
  • 4 The Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, Shandong, China.
  • 5 Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the People's Republic of China, Key Laboratory of Medical Cell Biology, Ministry of Education of the People's Republic of China, China Medical University, Shenyang 110122, Liaoning, China.
  • 6 Aging Institute, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA 15219.
  • # Contributed equally.
PMID: 41026812 DOI: 10.1073/pnas.2502841122
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.

Keywords

ATM; CHK2; PINK1; mitophagy; mtROS.

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