Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis
Abstract
Abstract Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.
Article Details
Authors (22)
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
Yang Guo
Department of Materials Science and Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon 999077, Hong Kong SAR, China
Ran Guo
Yong-Ze Li
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
Shuang Hao
The College of Basic Medical Science, Health Sciences Institute, China Medical University
Ye Zhang
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
Xiao-Xu Wu
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
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
Jia-Bin Li
Chen Liu
Liang Wang
Zhen-Hua Li
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry
Wei-Ping Teng
Zhong-Yan Shan
Liu Cao
Computational Biology Department, School of Computer Science
Qi-Qiang Guo
The College of Basic Medical Science, Health Sciences Institute, China Medical University