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 < 0.05). It also reduced the proportion of damaged mitochondria and mitochondrial ROS. In H/R-induced RTEC cells, deacetylation of IDH2 (K413) also decreased mitochondrial function, ROS and oxidative stress levels (p < 0.05). Additionally, we confirmed an interaction between IDH2 and SIRT3, and observed that IDH2 acetylation levels significantly increased in RIRI and H/R models (p < 0.01). After deacetylation of IDH2 (K413) treatment, acetylated IDH2 (K413) ratio, the expression levels of oxidative phosphorylation enzymes (II, III, and V), cleaved caspase-3, and phosphorylated-dynamin-related protein 1 (Ser616) were decreased, while SIRT3 and phosphorylated-DRP1(Ser637) expression increased (p < 0.05). SIRT3 overexpression alleviated cell apoptosis, decreased mitochondrial ROS, and restored mitochondrial membrane potential (p < 0.01).

Conclusion: Overexpressing SIRT3 may alleviate RIRI by deacetylating IDH2, providing a theoretical basis for the pathogenesis research of RIRI.