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Updated: Jan 7, 2026
A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation
Published on: July 13, 2018
Methylmalonate accumulation contributes to myocardial vulnerability post-reperfusion: a novel therapeutic target and
Shanjie Wang1,2, JunChen Guo1,2, Zeng Wang1,2
1Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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.
Insights
Methylmalonic acid (MMA) exacerbates myocardial injury after reperfusion, distinct from succinate. Targeting MMA metabolism may improve risk stratification and reduce heart damage in acute myocardial infarction patients.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Metabolic Disorders
Background:
- Mitochondrial dysfunction is key in myocardial ischemia-reperfusion (I/R) injury, yet clinical applications are limited.
- Methylmalonic acidemia, a metabolic disorder, causes severe mitochondrial damage.
- The role of methylmalonic acid (MMA) in I/R pathogenesis and its clinical relevance were previously unknown.
Purpose of the Study:
- To investigate the biological impact of MMA on myocardial I/R injury.
- To explore the translational relevance of targeting MMA metabolism in I/R.
- To compare MMA's effect with its isomer, succinate, in I/R.
Main Methods:
- Measured MMA and metabolites in human cohorts and animal models.
- Utilized mouse I/R models with endogenous MMA elevation (Mmut-conditional knockout) and exogenous MMA administration.
- Employed multiomics, ChIP, and mutagenesis assays to elucidate mechanisms; assessed therapeutic potential in a porcine I/R model.
Main Results:
- Circulating MMA levels predict post-reperfusion myocardial injury and heart failure risk, outperforming succinate in humans.
- Both MMA and succinate increased in early I/R mouse hearts, but MMA persisted while succinate normalized.
- MMA, not succinate, heightened I/R susceptibility and mitochondrial dysfunction, inhibiting SIRT1-CREB-BNIP3 signaling for mitochondrial quality control.
Conclusions:
- MMA has a detrimental effect on myocardial vulnerability, separate from succinate's role.
- Targeting MMA metabolism offers a potential strategy for risk stratification and mitigating myocardial injury in acute myocardial infarction (AMI).
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