Methylmalonate accumulation contributes to myocardial vulnerability post-reperfusion: a novel therapeutic target and prognostic biomarker.

Abstract

Dysfunctional mitochondria are a prominent feature of myocardial ischemic-reperfusion (I/R) injury, but the clinical translation is scarce. Congenital dysbolism methylmalonic acidemia causes fatal mitochondrial lesions and premature death. However, the biological impact of mitochondrial metabolite methylmalonic acid (MMA) in the pathogenesis of I/R and its translational relevance were unknown. MMA and relevant metabolites were measured in 3 independent human cohorts and animals. Cardiac Mmut-conditional knockout (endogenous MMA elevation) and exogenous MMA administration were conducted in mouse I/R model. The potential mechanism was explored through multiomics, chromatin immunoprecipitation, and site-directed mutagenesis assays. The translational value of targeting MMA metabolism was assessed in a porcine I/R model. Circulating MMA predicts myocardial injury or heart failure risk post-reperfusion, which outmatches its isomer succinate in humans. Both MMA and succinate were elevated in heart tissues of mice at the initial period post-I/R, while later, MMA maintained higher levels, but succinate rapidly decreased to baseline levels. Endogenous and exogenous MMA, not succinate, increased susceptibility to myocardial I/R injury and mitochondrial dyshomeostasis, including impaired mitochondrial bioenergetics, biogenesis, and renovation. Mechanistically, MMA elevation inhibited the deacetylase activity of SIRT1; thus, hyperacetylation of transcription factor CREB^K309 blunted its binding to the BNIP3 promoter and inhibited BNIP3-mediated mitochondrial quality control. Adeno-associated virus 9-containing MMUT gene delivery ameliorated impaired MMA metabolism to improve mitochondrial quality and cardiac phenotypes in I/R pigs. This study revealed an unrecognized harmful effect of MMA on myocardial vulnerability distinct from its isomer succinate. Targeting MMA metabolism represents a promising strategy to optimize risk stratification and mitigate myocardial injury in patients with AMI.