IDH2 lactylation regulates mitochondrial dysfunction injury induced by myocardial ischemia‑reperfusion via the AMPK signaling pathway

Ischemic cardiomyopathy ranks as a principal cause of death and incapacity worldwide. Myocardial ischemia‑reperfusion injury (MIRI) caused by percutaneous coronary intervention is a major threat in the treatment of ischemic cardiomyopathy. Although lactylation (Kla) is extensively implicated in numerous pathological processes, its role and specific effects in MIRI remain unclear. Lactylation proteomics was used to identify proteins with different modifications during ischemia‑reperfusion injury. Co‑immunoprecipitation experiments were utilized to detect isocitrate dehydrogenase 2 (IDH2) lactylation levels. Immuno­fluorescence staining was applied to confirm intracellular lactylation levels. TUNEL, DHE and MitoSOX staining were used to measure oxidative damage in cells and tissues. An oxygen consumption rate experiment and the ATP assay were conducted to determine mitochondrial function. Western blots were utilized to detect changes in proteins related to mitochondrial functional homeostasis and downstream signal alterations. Excessive lactate accumulation was observed in MIRI model mice. This accumulation exacerbated the decline in cardiac function and the damage to cardiomyocytes in mice after MIRI. The lactylation of IDH2 in mitochondria was found to play a regulatory role in mitochondrial dysfunction and MIRI. Regarding the mechanism, it was verified that high IDH2 K275 lactylation caused a reduction in its enzymatic activity and decreased the production of α‑ketoglutarate in the tricarboxylic acid cycle. Consequently, the activation of the AMPK pathway was inhibited, and mitochondrial damage and functional impairment were aggravated. It was also found that SIRT3 regulated and prevented IDH2 lactylation. The results of the present study indicated that IDH2 lactylation, which is elevated due to lactate accumulation and negatively regulated by SIRT3, contributes to the exacerbation of MIRI by regulating the functional homeostasis of mitochondria. This discovery offers a new therapeutic concept and target for MIRI prevention.