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

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.