Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and...

Aortic dissection (AD) is a cardiovascular disorder with a high mortality rate. Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modification omics, we conducted a macroscopic analysis of the occurrence of extensive lactylation modification in aortic dissection and identified extensive lactylation, particularly in the adenosine triphosphatase activity pathway. Among these proteins, adenosine triphosphate (ATP) synthase F1 subunit α (ATP5F1A), a subunit in the ATP synthase complex, exhibited pronounced lactylation at the K531, catalyzed by sirtuin 3 (Sirt3). Through site-directed mutagenesis (K531R/K531E), we validated the key mechanism of lactylation activation at the K531 site of ATP5F1A and the regulatory enzymes. Functionally, K531 lactylation impairs ATP synthase activity, elevates reactive oxygen species generation, reduces ATP generation, and induces mitochondrial structural abnormalities. These effects ultimately contribute to the phenotypic transformation of human aortic vascular smooth muscle cells and enhanced synthesis and secretion of matrix metalloproteinases. In addition, we assessed the potential therapeutic effect of lactylation inhibition in aortic dissection using a mouse model and a drug based in vivo lactate alteration strategy. In conclusion, targeting the lactate-Sirt3-ATP5F1A axis represents a promising therapeutic strategy for blocking the progression of aortic dissection.