Zn2+ regulates mitochondrial DNA efflux to inhibit AIM2-mediated ZBP1-PANoptosome pathway and alleviate septic myocardial injury

  • Chem Biol Interact. 2025 Aug 25:417:111525. doi: 10.1016/j.cbi.2025.111525.
Jun Guo  1 ,  Shanshan Meng  2 ,  Jin Zhang  2 ,  Ni Wang  2 ,  Fengmei Guo  3
Affiliations
  • 1. Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, PR China; Department of Critical Care Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430014, Hubei Province, PR China.
  • 2. Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, PR China.
  • 3. Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, PR China. Electronic address: [email protected].
PMID: 40348119 DOI: 10.1016/j.cbi.2025.111525
Abstract

This study was performed to investigate the mechanism by which zinc ion regulated mitochondrial DNA (mtDNA) efflux to inhibit the AIM2-mediated ZBP1-PANoptosome pathway and alleviate sepsis-induced myocardial injury. Here we discovered that zinc ions suppressed mitochondrial DNA release, thereby protecting the heart from LPS-induced damage in mice. In addition, LPS induced mPTP opening and mediated mtDNA efflux in cardiomyocytes, which drove AIM2 activation and ZBP1-PANoptosome multiprotein complex formation, leading to pan-apoptotic cardiomyocyte death. Zn2+ prevented mPTP opening to inhibit mtDNA efflux-driven AIM2 and ZBP1-PANoptosome multiprotein complex formation and alleviate PANoptosis. Knockdown of AIM2 alleviated LPS-induced PANoptosis in cardiomyocytes. LPS-induced PANoptosis in cardiomyocytes by regulating the ZBP1/RIPK3 pathway. However, activation of the ZBP1/RIPK3 pathway partially reversed the inhibitory effect of Zn2+ on PANoptosis in cardiomyocytes. Taken together, Zn2+ regulated mitochondrial DNA efflux to inhibit the AIM2-mediated ZBP1-PANoptosome pathway to alleviate septic myocardial injury.

Keywords
Mitochondrial DNA efflux; PANoptosis; Sepsis-induced cardiomyopathy; ZBP1-PANoptosome pathway; Zn(2+).
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