ArticleCell communication and signaling : CCS2024
Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis.
Article in Cell communication and signaling : CCS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 34 citations in OpenAlex.
- Exosomes derived from AHR-overexpressing human umbilical cord mesenchymal stem cells attenuate H/R injury via AHR/NLRP3 pathway.Cell cycle (Georgetown, Tex.) · 2026Article
- Plasma metabolomic profiling reveals metabolic shifts linked to growth depression in broilers fed high level of valine.Poultry science · 2026Article
- Baicalin Protects ARPE-19 Cells Against BRVO-Related Hypoxic Injury by Preserving Mitochondrial Function and Inhibiting Ferroptosis.Antioxidants (Basel, Switzerland) · 2026Article
- The mediating role of inflammation and nutrition metabolism in the methylmalonic acid-stroke association.Clinics (Sao Paulo, Brazil) · 2026Article
- Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K-NF-κB pathway drives M1 macrophage polarization in renal ischemia-reperfusion injury.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Knockdown of Transthyretin ameliorates ferroptosis in myocardial ischemia-reperfusion injury.Molecular biology reports · 2026Article
- Harnessing the novel safeguarding role of Selenoprotein T in age-related myocardial left and right decline through the ferroptosis-mitochondrial axis.Journal of translational medicine · 2026Article
- Targeting the GPX4-FUNDC1 Interaction with Magnesium Lithospermate B Attenuates Sepsis-Associated Lung Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Electroacupuncture preconditioning alleviates myocardial ischemia-reperfusion injury through reducing the inflammatory response mediated by the miR-146a/TRAF6/IRAK4 pathway.Iranian journal of basic medical sciences · 2026Article
- Targeted Delivery of Schisandrin A to Cardiac Endothelium Alleviates Myocardial Ischemia-Reperfusion Injury via Suppression of Ferroptosis.International journal of nanomedicine · 2026Article
- Methylmalonate accumulation contributes to myocardial vulnerability post-reperfusion: a novel therapeutic target and prognostic biomarker.BMC medicine · 2025Article
- Association between methylmalonic acid and prevalence of depression in US adults: evidence from NHANES 2011-2014.European journal of psychotraumatology · 2025Article
- Recent research advances in the biological function and molecular mechanism of methylmalonic acid.Journal of Zhejiang University. Science. B · 2025Review
- Serum methylmalonic acid levels predict multisite bone mineral density decline in patients with suspected mitochondrial dysfunction.Journal of orthopaedic surgery and research · 2025Article
- From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review).International journal of oncology · 2025Review
- The Role of Methylmalonic Acid in the Risk of Sarcopenia and All-Cause Mortality Among Individuals With Sarcopenia: Evidence From NHANES.Food science & nutrition · 2025Article
- The interaction between ferroptosis and myocardial ischemia-reperfusion injury: molecular mechanisms and potential therapeutic targets.European journal of medical research · 2025Review
- RBM15 promotes hypoxia/reoxygenation-induced ferroptosis in human cardiomyocytes by mediating m6A modification of ACSL4.Hereditas · 2025Article
- Targeting the ROCK2/UBA52/DRP1 axis enhances ferroptosis and overcomes pemigatinib resistance in Cholangiocarcinoma.Cell death & disease · 2025Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.
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