Jun Guo, Shanshan Meng, Jin Zhang, Ni Wang, Fengmei Guo
{"title":"Zn2+调节线粒体DNA外排，抑制aim2介导的ZBP1-PANoptosome通路，减轻脓毒性心肌损伤。","authors":"Jun Guo, Shanshan Meng, Jin Zhang, Ni Wang, Fengmei Guo","doi":"10.1016/j.cbi.2025.111525","DOIUrl":null,"url":null,"abstract":"<p><p>This study was performed to investigate the mechanism by which zinc ion regulated 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. Zn<sup>2+</sup> 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 Zn<sup>2+</sup> on PANoptosis in cardiomyocytes. Taken together, Zn<sup>2+</sup> regulated mitochondrial DNA efflux to inhibit the AIM2-mediated ZBP1-PANoptosome pathway to alleviate septic myocardial injury.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111525"},"PeriodicalIF":0.0000,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Zn<sup>2+</sup> regulates mitochondrial DNA efflux to inhibit AIM2-mediated ZBP1-PANoptosome pathway and alleviate septic myocardial injury.\",\"authors\":\"Jun Guo, Shanshan Meng, Jin Zhang, Ni Wang, Fengmei Guo\",\"doi\":\"10.1016/j.cbi.2025.111525\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>This study was performed to investigate the mechanism by which zinc ion regulated 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. Zn<sup>2+</sup> 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 Zn<sup>2+</sup> on PANoptosis in cardiomyocytes. Taken together, Zn<sup>2+</sup> regulated mitochondrial DNA efflux to inhibit the AIM2-mediated ZBP1-PANoptosome pathway to alleviate septic myocardial injury.</p>\",\"PeriodicalId\":93932,\"journal\":{\"name\":\"Chemico-biological interactions\",\"volume\":\" \",\"pages\":\"111525\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemico-biological interactions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cbi.2025.111525\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-biological interactions","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cbi.2025.111525","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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 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.
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