SIRT3 attenuates sepsis-induced EndMT and cardiac remodeling by facilitating mitophagy process via PINK1/Parkin signaling

Endothelial-mesenchymal transition (EndMT) is a key contributor to the progression of sepsis-induced myocardial injury (SIMI). Defective mitophagy can result in oxidative stress and mitochondrial dysfunction, both of which play a critical role in EndMT. Sirtuin 3 (SIRT3), a major deacetylase responsible for mitochondrial quality control, has the potential to regulate EndMT, although the exact mechanism remains unclear. Therefore, this study aims to investigate the role of SIRT3 in mediating EndMT and cardiac remodeling during SIMI. Wild-type and SIRT3 knockout mice were induced with lipopolysaccharide (LPS) for 24-h to mimic SIMI. Human cardiac microvascular endothelial cells were treated with LPS for in vitro experiments. Cardiac function was measured by echocardiography. Cardiac fibrosis was determined by Sirus red and Masson's trichrome staining. The expression of endothelial biomarkers and mesenchymal biomarkers was detected using immunofluorescence and western blot to determine EndMT. Mitochondria function and mitophagy were determined by transmission electron microscopy (TEM) and protein biomarkers. The interaction of SIRT3 with PINK1/Parkin was detected by immunoprecipitation (IP) and co-IP. Following endotoxin exposure, SIRT3 knockout mice exhibited a more severe EndMT phenotype and increased collagen deposition in cardiac tissues, along with mitochondrial dysfunction and impaired mitophagy. Similarly, LPS treatment induced mitochondrial oxidative stress and disrupted mitophagy flux during EndMT in CMECs, effects that were partially rescued by either rapamycin treatment or SIRT3 upregulation. Furthermore, SIRT3 overexpression enhanced deacetylation of the PINK1/Parkin pathway, thereby promoting mitophagy. Our findings suggest that SIRT3 suppresses EndMT-mediated cardiac fibrosis by promoting PINK1/Parkin-dependent mitophagy, offering novel insights for the treatment of SIMI.