SIRT3-FOXO3a Isoforms Forge Nuclear–Mitochondrial Links to Combat Sepsis-Induced Cardiomyopathy Oxidative Stress in Mice

Aims: Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis. The relationship between SIC and protein acetylation, particularly the balance between acetylation and deacetylation in cardiomyocyte subcellular structures, as well as how nuclear-mitochondrial coordination maintains standard antioxidant stress capacity, remains unclear. This study focused on exploring the nuclear-mitochondrial regulatory mechanisms formed by the interplay of Sirtuin 3 (SIRT3) and Forkhead box O3a (FOXO3a). Results: In vivo, SIC markers increased significantly in wild-type CLP (Cecal Ligation and Puncture) mice at 72 h (CLP72h) but were partially reversed in CLP72h+oeSIRT3 mice. CLP72h mice exhibited significantly reduced mitochondrial area, aspect ratio, and mtDNA copy number. Echocardiography revealed significantly impaired cardiac function. Western blotting showed significantly decreased nuclear and mitochondrial long-form SIRT3, nuclear long-form and mitochondrial short-form FOXO3a, and mitochondrial superoxide dismutase 2 (SOD2), with significantly increased acetylation in CLP72h mice. In vitro, oeSIRT3 preserved nuclear FOXO3a localization and mitochondrial membrane potential, with CLP72h+oeSIRT3 mice showing significantly reduced oxidative stress. The long form of SIRT3 plays a crucial deacetylation role in SIC and influences SOD2 partially through FOXO3a. Innovation: This study explored the roles of different SIRT3 and FOXO3a isoforms in combating oxidative stress in SIC through dynamic nucleus-mitochondrial regulation. Conclusion: This study underscores the critical role of the SIRT3-FOXO3a axis in enhancing mitochondrial antioxidant capacity through a nuclear-mitochondrial network during SIC, offering new insights into molecular mechanisms and potential therapeutic strategies for SIC. Antioxid. Redox Signal. 00, 000-000.