Lactylation: Metabolic epigenetic regulation and cell death mechanisms in myocardial ischemia‒reperfusion injury

Figures

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  Figure 1. Schematic overview of lactate metabolism in the heart. In response to ischemia, hypoxia, and metabolic disorders, lactate production increases in cardiomyocytes and enters the cells through MCT1. Glucose enters the cytoplasm via glucose transporters (Glut) and is metabolized into pyruvate. Under normoxic conditions, pyruvate is transported into mitochondria, where pyruvate dehydrogenase (PDH) converts it into acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle for energy production. However, under hypoxic conditions, lactate dehydrogenase A (LDHA) facilitates the conversion of pyruvate into lactate. Furthermore, lactate serves as an important substrate for lysine Kla, a modification that affects both histone and non-histone proteins, ultimately regulating various cellular processes.

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  Figure 2. Potential mechanism of histone lysine lactylation (Kla)-related- post-translational modifications (PTMs) regulating cell death in myocardial ischemia/reperfusion injury (MI/RI). Lactate elevates MICU3 levels by promoting H3K18la modification in the MICU3 promoter region, concurrently enhancing its interaction with AASR1. Upregulated MICU3 binds to VDAC1 to promote mitochondrial autophagy in MI/RI. Furthermore, MICU3 knockout increases pyruvate dehydrogenase (PDH) phosphorylation levels, thereby attenuating MI/RI. This suggests a potential link between Kla and phosphorylation in regulating mitochondrial autophagy. Accumulated lactate in MI/RI enhances the expression of the m6A reader protein YTHDF2 by promoting Kla, which in turn boosts G3BP1 expression and ultimately attenuates apoptosis. This reveals a potential connection between Kla and m6A in regulating apoptosis during MI/RI. The lactylase modifier KAT5 promotes LATS2 protein ubiquitination and degradation by acetylating STUB1, thereby inhibiting NLRP3-mediated pyroptosis to mitigate MI/RI. This suggests a regulatory role for Kla in pyroptosis via acetylation and ubiquitination pathways. Dexamethasone (Dex) suppresses iron…