ArticleNature2014
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,631 papers, 1 of them a synthesis that pooled it.
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Who cites it
1,631 citing papers in PubMed, 1 synthesis or guideline pooled it, 2,713 citations in OpenAlex.
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- Mitochondrial dysfunction in microglia: a novel perspective of depression pathogenesis.Inflammation and regeneration · 2026Review
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- Cardioprotection Is a Delivery Problem: A First-Medical-Contact Framework for Acute Myocardial Infarction.ACS pharmacology & translational science · 2026Article
- Loss of O-GlcNAc transferase activity impairs the dynamic formation of protective stress granules in ischemic cardiomyocytes.The Biochemical journal · 2026Article
- A roadmap towards clinical use of molecular biomarkers in acute ischaemic stroke.Nature reviews. Neurology · 2026Review
- Mitochondrial calcium and ROS: present understanding and future directions.Mitochondrion · 2026Article
- Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease.Brain : a journal of neurology · 2026Review
- Metabolic dependency of malonate protection against cardiac ischemia-reperfusion injury.Basic research in cardiology · 2026Article
- A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.Nature cardiovascular research · 2026Article
- Cell death in ischemia-reperfusion injury: beyond a single-cell-death perspective.Biomarker research · 2026Review
- Aglycemia triggers alternative electron transport to sustain mesenchymal stem cell survival under anoxia.Redox biology · 2026Article
- Fumarate and Its Esters: Physiology, Pathology, Molecular Mechanisms, Diseases, and Therapy.MedComm · 2026Review
- H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Flow Cytometry and AI-Driven Biomarker Discovery in Acute Kidney Injury: From Mechanistic Insights to Translation Applications in Clinical and Austere Environments.International journal of molecular sciences · 2026Review
- White Wine Intake Reduces Mitochondrial Complex I-Derived ROS in the Male Rat Heart.Antioxidants (Basel, Switzerland) · 2026Article
- Ferroptosis-Mitochondrial Crosstalk in Cardiomyocyte Death: The Cardiomyocyte Ferroptotic Amplification Circuit (CFAC) as a Proposed, Testable Systems Framework.Cardiovascular toxicology · 2026Review
1,571 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 7 institutions in 2 countries.
Funding
Abstract
Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.
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Registered trials
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.