SIRT3-mediated Deacetylation of IDH2 Reduces Mitochondrial Dysfunction and Improves Renal Ischemia-reperfusion Injury

Background: Renal ischemia-reperfusion injury (RIRI) is characterized by increased reactive oxygen species (ROS) and mitochondrial damage. Sirtuin 3 (SIRT3) promotes the deacetylation of isocitrate dehydrogenase 2 (IDH2) at lysine 413 (K413), thereby maintaining mitochondrial homeostasis. However, the roles of SIRT3 and IDH2 in RIRI remain unclear. Methods: RIRI mouse models and hypoxia-reoxygenation (H/R)-exposed primary renal tubular epithelial cells (RTECs) were established, combined with adeno-associated virus and plasmid. Biochemical reagent kits, ELISA kits, hematoxylin and eosin staining, Transmission electron microscope, flow cytometry, Cell counting kit 8, co-immunoprecipitation and western blot assay were used. The role of SIRT3 overexpression in H/R-induced RTEC injury was investigated by plasmid transfection. Results: Deacetylation of IDH2 (K413) ameliorated renal pathological damage and suppressed kidney injury indicators, malondialdehyde levels, and nicotinamide adenine dinucleotide (NAD) phosphate+/NAD phosphate hydrogen ratio, while increasing superoxide dismutase activity, glutathione/glutathione disulfide ratio, NAD-IDH activity, and ATP levels (p p p p p < 0.01). Conclusion: Overexpressing SIRT3 may alleviate RIRI by deacetylating IDH2, providing a theoretical basis for the pathogenesis research of RIRI.