MCT1 inhibition with AZD3965 reshapes the mitochondrial lactylome post-myocardial infarction, attenuating fibrosis and inflammation and partially restoring respiration despite impaired global function.
Mitochondrial lactylation acts as a context-dependent regulator of metabolism and redox balance post-MI, and MCT1 inhibition can reduce fibrosis and inflammation, highlighting metabolic plasticity as a potential therapeutic target.
Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease. • Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 proteins show elevated lactylation. • MCT1 inhibition reshapes the mitochondrial lactylome, increasing lactylation of specific proteins. • MI and MCT1 inhibition remodel TCA, amino acid, and gene expression pathways. • AZD3965 reduces fibrosis/inflammation and partly restores respiration post-MI, not function.
Kadam et al. (Fri,) conducted a other in Myocardial infarction. MCT1 inhibition (AZD3965) was evaluated on Mitochondrial protein lactylation, fibrosis, inflammation, and mitochondrial respiratory capacity. MCT1 inhibition with AZD3965 reshapes the mitochondrial lactylome post-myocardial infarction, attenuating fibrosis and inflammation and partially restoring respiration despite impaired global function.