ArticleJournal of the American Heart Association2022
Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation.
Article in Journal of the American Heart Association, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 35 citations in OpenAlex.
- Mitochondrial oxidative stress, calcium and dynamics in cardiac ischaemia-reperfusion injury.The Journal of physiology · 2026Review
- Lactylation landscape of mitochondrial proteins in myocardial infarction.Redox biology · 2026Article
- Metabolic inflexibility across heart failure phenotypes: mechanisms and type-specific therapeutic implications.Apoptosis : an international journal on programmed cell death · 2026Review
- Mechanisms Involved in Pathological Succinate-Mediated Signaling.International journal of molecular sciences · 2026Review
- Lactylation landscape of mitochondrial proteins in myocardial infarction.bioRxiv : the preprint server for biology · 2026Article
- The role and therapeutic potential of succinate and succinylation in cardiovascular diseases.Clinical epigenetics · 2026Review
- Plasma and pericardial fluid metabolomic signatures of patients with ischemic heart disease.Communications medicine · 2026Article
- The immune-cardiovascular metabolic circuitry in myocardial ischemia-reperfusion injury: from metabolic signal release to spatiotemporal reprogramming.Frontiers in immunology · 2026Review
- Increased fasting plasma succinate levels are associated with higher resting heart rate in young sedentary adults.Frontiers in physiology · 2026Article
- Integrating Senescence and Oxidative Stress in Cardiac Disease.International journal of molecular sciences · 2025Review
- Femoral arteriovenous concentration differences reveal metabolomic shifts in peripheral artery disease (PAD): A case-control study.Vascular medicine (London, England) · 2025Article
- Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.Nature cardiovascular research · 2025Article
- Succinate Dehydrogenase Subunit A (SDHA) Mediated Microglia Extracellular Traps Formation Participating in Cerebral Ischemic Reperfusion Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Type 2 diabetes worsens the outcome of ischemia/reperfusion in female STEMI patients and female db/db mice with HFpEF cardiometabolic phenotype.Cardiovascular diabetology · 2025Article
- Mitochondrial Dysfunction in Cardiac Surgery.Anesthesiology clinics · 2025Review
- Transplantation of exogenous mitochondria mitigates myocardial dysfunction after cardiac arrest.eLife · 2025Article
- Brief hypothermic oxygenated perfusion provides cardioprotection in a pig model of donation after circulatory death.European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery · 2025Article
- Mitochondria and myocardial ischemia/reperfusion injury: Effects of Chinese herbal medicine and the underlying mechanisms.Journal of pharmaceutical analysis · 2025Review
- Article
- Unveiling the Renoprotective Mechanisms of Schisandrin B in Ischemia-Reperfusion Injury Through Transcriptomic and Pharmacological Analysis.Drug design, development and therapy · 2024Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Background The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia-reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury. Methods and Results Using the mitochondrial ROS probe mitoSOX and a custom-built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition. Conclusions Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.