Uqcrc2 lactylation promotes sepsis-induced cardiomyopathy by targeting the mitochondrial respiratory chain

Sepsis-induced cardiomyopathy (SIC) markedly increases the overall mortality among patients with sepsis. The pathogenesis of SIC remains incompletely elucidated; specifically, the role of protein lactylation in the onset and progression of SIC awaits further investigation.

Using lactylome profilinganalysis, bioinformatics and molecular biology methods, the key proteins and lactylation sites involved in the development of SIC were identified. Amino acid point mutations, molecular dynamic simulation, and biochemical experiments were performed to investigate their biological roles and underlying mechanisms.

The lactylome analysis revealed 439 differentially lactylated sites in the myocardium of septic mice compared with control group.Through integrated bioinformatic analysis and molecular validation, we demonstrated that lactylation of ubiquinol-cytochrome c reductase core protein 2 (Uqcrc2) plays a pivotal role in SIC, andidentified K109 as the critical lactylation site. Mechanistically,Uqcrc2 K109 lactylation disrupts mitochondrial respiratory chain function and exacerbates cardiomyocyte apoptosis. Importantly,inhibition of Uqcrc2 K109 lactylation attenuates this apoptotic process. Furthermore, we identifiedlysine acetyltransferase 6A (KAT6A) as a novel lactyltransferase, mediating Uqcrc2 lactylation.

Our study reveals that the lactate-KAT6A-Uqcrc2 lactylation-mitochondrial apoptosis axis plays a pivotal role in SIC.