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Background <p>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.</p> Methods <p>MMA and relevant metabolites were measured in 3 independent human cohorts and animals. Cardiac <i>Mmut</i>-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.</p> Results <p>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<sup>K309</sup> blunted its binding to the BNIP3 promoter and inhibited BNIP3-mediated mitochondrial quality control. Adeno-associated virus 9-containing <i>MMUT</i> gene delivery ameliorated impaired MMA metabolism to improve mitochondrial quality and cardiac phenotypes in I/R pigs.</p> Conclusions <p>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.</p> Graphical Abstract <p>Compared with its well-known isomer succinate, the mitochondria-derived metabolite MMA is more robustly associated with myocardial injury post-reperfusion in both humans and animals. An increase in MMA but not succinate increased myocardial susceptibility and mitochondrial dysfunction under I/R conditions via inhibiting SIRT1/CREB/BNIP3-mediated mitochondrial quality control. In large animal experiments, promoting MMA metabolism through in vivo injection of AAV9-containing MMUT significantly mitigated the infarct size, mitochondrial dysfunction, and cardiac remodeling post-I/R. HF, heart failure; MI, myocardial infarction; CVD, cardiovascular disease.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Shanjie Wang,
  • JunChen Guo,
  • Zeng Wang,
  • Kegong Chen,
  • Xiaoxuan Liu,
  • Yan Cui,
  • Ye Wang,
  • Zhaoying Li,
  • Hengxuan Cai,
  • Guanpeng Ma,
  • Zhenming Zhang,
  • Guokun Wang,
  • Lili Xiu,
  • Shuijie Li,
  • Hulun Li,
  • Haibo Jia,
  • Bo Yu,
  • Shaohong Fang

摘要

Background

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.

Methods

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.

Results

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 CREBK309 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.

Conclusions

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.

Graphical Abstract

Compared with its well-known isomer succinate, the mitochondria-derived metabolite MMA is more robustly associated with myocardial injury post-reperfusion in both humans and animals. An increase in MMA but not succinate increased myocardial susceptibility and mitochondrial dysfunction under I/R conditions via inhibiting SIRT1/CREB/BNIP3-mediated mitochondrial quality control. In large animal experiments, promoting MMA metabolism through in vivo injection of AAV9-containing MMUT significantly mitigated the infarct size, mitochondrial dysfunction, and cardiac remodeling post-I/R. HF, heart failure; MI, myocardial infarction; CVD, cardiovascular disease.