The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Together, these conditions promote reverse electron transfer upon reperfusion, which results in significant superoxide production from complex I (171).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [171]
In the citing paper
“This type of ROS generation occurs when succinate, the substrate for complex II, is present in high concentration and is responsible in vivo for the ROS generated after ischemia upon reperfusion (171, 172).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [171]
In the citing paper
“α-KG and succinate can regulate the activity of other members of the α-KGDD family of enzymes, in particular those involved in the regulation of histone and DNA demethylation, the α-KG-dependent Jumonji C-domain containing histone demethylases (JMJDs) and the Ten eleven translocation (TET) family of 5mC hydroxylases, which play a role in DNA demethylation.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [33]
In the citing paper
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13,25,40,41).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [41]
In the citing paper
“Notably, SDH inhibition protected against brain injury after ischemia/reperfusion (40,41), suggesting that inhibition of SDH by endogenously produced itaconate may buffer against potential oxidative damage that can occur under such conditions.”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Self-citationSuccinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176
Self-citationWhat is flux balance analysis?
Orth, J. D., Thiele, I., & Palsson, B. Ø. (2010) · Nature Biotechnology · doi:10.1038/nbt.1614 · Cited by 3,903
Yellon, D. M., & Hausenloy, D. J. (2007) · New England Journal of Medicine · doi:10.1056/nejmra071667 · Cited by 3,797
Ischemia and reperfusion—from mechanism to translation
Eltzschig, H. K., & Eckle, T. D. L. G. (2011) · Nature Medicine · doi:10.1038/nm.2507 · Cited by 3,468
Srere, P. A. (1969) · Methods in Enzymology · doi:10.1016/0076-6879(69)13005-0 · Cited by 2,005
Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0
Schellenberger, J., Que, R., Fleming, R. M. T., Thiele, I., Orth, J. D., Feist, A. M., Zielinski, D. C., Bordbar, A., Lewis, N. E., Rahmanian, S., et al. (2011) · Nature Protocols · doi:10.1038/nprot.2011.308 · Cited by 1,835
Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury
Murphy, E., & Steenbergen, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00024.2007 · Cited by 1,504
Pacher, P., Nivorozhkin, A., & Szabó, C. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.1.6 · Cited by 1,218
Direct measurement of free radical generation following reperfusion of ischemic myocardium.
Zweier, J. L., Flaherty, J. T., & Weisfeldt, M. L. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.5.1404 · Cited by 1,189
Cited by
Sorted by citations
Items 901–1,000 of 1,003
Larrea, D., Tamucci, K. A., Kabra, K., VELASCO, K. R., Yun, T. D., Pera, M., Montesinos, J., Agrawal, R. R., Paradas, C., Smerdon, J. W., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-51578-1 · Cited by 46
“The fi rst-rate order constant of the D-form to A-form transition was calculated in R version 3.4 (RStudio, Posit PBC) using semilogarithmic plots as described previously 19 .”
InfluentialIschemia - Reperfusion injury: A roadmap to precision therapies
Li, W., Yan, L., Chen, J., Kang, W., Wang, X., Zhai, X., Xue, Y., Zhang, W., Xia, Y., & Cui, D. (2025) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2025.101382 · Cited by 45
Yoshihara, H. A. I., Bastiaansen, J., Berthonneche, C., Comment, A., & Schwitter, J. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00376.2015 · Cited by 39
Mailloux, R. J., Young, A., Chalker, J., Gardiner, D., O’Brien, M., Slade, L., & Brosnan, J. T. (2016) · FEBS Letters · doi:10.1002/1873-3468.12461 · Cited by 37
Role of glycogen synthase kinase following myocardial infarction and ischemia–reperfusion
Ghaderi, S., Alidadiani, N., Dilaver, N., Heidari, H. R., Parvizi, R., Rahbarghazi, R., Soleimanirad, J., & Baradaran, B. (2017) · APOPTOSIS · doi:10.1007/s10495-017-1376-0 · Cited by 39
New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma
Taïeb, D., & Pacák, K. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.08.001 · Cited by 40
Metabolism and inflammation: implications for traumatic brain injury therapeutics
Killen, M. J., Giorgi-Coll, S., Helmy, A. E., Hutchinson, P. J., & Carpenter, K. L. H. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1582332 · Cited by 39
“build up in tissue, leading to the production of excessive reactive oxygen species (ROS) when oxygen is returned [131,133].”
BackgroundRookyard, A. W., Paulech, J., Thyssen, S., Liddy, K. A., Puckeridge, M., Li, D. K., White, M. Y., & Cordwell, S. J. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7765 · Cited by 39
“While reperfusion is critical to survival posthypoxia, it comes with the burden of an influx of ROS generated by uncoupling of mitochondrial electron transport, elevated succinate, reduced antioxidant activity, and immune cell infiltration (2, 11, 14, 60).”
Targeting NOX 4 by petunidin improves anoxia/reoxygenation-induced myocardium injury
Cai, X., Yang, C., Shao, L., Zhu, H., Wang, Y., Huang, X. B., Wang, S., & Hong, L. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173414 · Cited by 39
Park, E., Dusabimana, T., Je, J., Jeong, K., Yun, S. P., Kim, H. J., Kim, H. J., & Park, S. W. (2020) · Biomedicines · doi:10.3390/biomedicines8090352 · Cited by 39
“The kidney tissues exposed IR presented a substantial accumulation of XO substrates (hypoxanthine, xanthine, and succinate) [4] and the XO inhibitors (e.”
BackgroundThe Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View
Vezzani, B., Carinci, M., Patergnani, S., Pasquin, M., Guarino, A., Aziz, N., Pinton, P., Simonato, M., & Giorgi, C. (2020) · Biomolecules · doi:10.3390/biom10101437 · Cited by 40
“By reverse electron transport, the oxidized metabolite promotes ROS formation at the complex I, providing the initiating burst of O2•− that leads to IR injury [216].”
BackgroundSuccinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS
Nunns, G. R., Vigneshwar, N., Kelher, M. R., Stettler, G. R., Gera, L., Reisz, J. A., D’Alessandro, A., Ryon, J., Hansen, K. C., Gamboni, F., et al. (2020) · Annals of Surgery · doi:10.1097/sla.0000000000004644 · Cited by 39
“Succinate may mediate ischemia-reperfusion injury by generating reactive oxygen species through reverse electron flow, although its primary role in this process has been questioned.(7,16,48) Succinate activation of the SUCNR1 receptor activates dendritic cells, has pro-inflammatory effects in the kidney and small inte…”
BackgroundInfluentialShi, C., Guo, H., & Liu, X. (2021) · Cell Transplantation · doi:10.1177/09636897211024210 · Cited by 40
Lohmann, S., Grigoletto, J., Bernis, M. E., Pesch, V., Ma, L., Reithofer, S., & Tamgüney, G. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01327-6 · Cited by 42
“Reoxygenation of ischemic tissue during reperfusion further enhances the detrimental primary effects of ischemia by an increase of neurotoxic reactive oxygen and nitrogen species [13, 21].”
BackgroundSu, X., Zhou, M., Li, Y., Zhang, J., An, N., Yang, F., Zhang, G., Yuan, C., Chen, H., Wu, H., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112893 · Cited by 40
Attaway, A. H., Bellar, A., Mishra, S., Karthikeyan, M., Sekar, J., Welch, N., Musich, R., Singh, S. S., Kumar, A., Menon, A., et al. (2023) · The Journal of Physiology · doi:10.1113/jp283700 · Cited by 45
“Reperfusion then causes succinate to be re-oxidized by succinate dehydrogenase (Chouchani et al., 2014).”
BackgroundAconitate decarboxylase 1 suppresses cerebral ischemia-reperfusion injury in mice
Vigil, T. M., Frieler, R. A., Kilpatrick, K. L., Wang, M. M., & Mortensen, R. M. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113902 · Cited by 39
Haleckova, A., Benek, O., Zemanová, L., Doležal, R., & Musílek, K. (2022) · Medicinal Research Reviews · doi:10.1002/med.21892 · Cited by 38
“A similar effect of CypD inhibition was also described in ischemic stroke(9) and hepatic IRI.(10,11) Neurodegenerative diseases, including Alzheimer ́s disease (AD) and multiple sclerosis,(15) represent another”
BackgroundCellular senescence in ischemia/reperfusion injury
Chen, C., Zheng, M., Hou, H., Fang, S., Chen, L., Yang, J., Yao, W., Zhang, Q., & Hei, Z. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01205-z · Cited by 41
Nanadikar, M. S., Leon, A. M. V., Guo, J., van Belle, G. J., Jatho, A., Philip, E. S., Brandner, A. F., Böckmann, R. A., Shi, R., Zieseniß, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37744-x · Cited by 38
Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction
Tu, C., Caudal, A., Liu, Y., Gorgodze, N., Zhang, H., Lam, C. K., Dai, Y., Zhang, A., Wnorowski, A. N., Wu, M. A., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01134-x · Cited by 38
The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke
Delgado‐Martín, S., & Martı́nez-Ruiz, A. (2024) · FEBS Letters · doi:10.1002/1873-3468.14894 · Cited by 42
“…have been described to take part in ischemia – reperfusion injury, including succinate accumulation and complex I deactivation during the ischemia that trigger an alteration of electron flux in the mitochondrial electron transport chain during reperfusion lined to increased ROS production [67 – 69].”
Abe, J., Vujić, A., Prag, H. A., Murphy, M. P., & Krieg, T. (2024) · Basic Research in Cardiology · doi:10.1007/s00395-024-01063-z · Cited by 37
“Malonate is protective in MI by blocking mitochondrial succinate oxidation by SDH; this prevents the burst of reactive oxygen species (ROS) production by reverse electron transport (RET) at mitochondrial complex I, which initiates the damage in IRI [4, 5, 20, 23].”
BackgroundMethodSelf-citationArndt, S., Baeza-Garza, C. D., Logan, A., Rosa, T., Wedmann, R., Prime, T. A., Martin, J. L., Saeb‐Parsy, K., Krieg, T., Filipović, M. R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.784678 · Cited by 38
“To extend this, we next focused on the heart as its metabolism changes dramatically upon ischemia (62, 63).”
Self-citationWang, Y.-H., Li, S.-A., Huang, C.-H., Su, H.-H., Chen, Y., Chang, J. T., & Huang, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00636 · Cited by 37
Chou, C., Fu, T., Tsai, H.-H., Hsu, C., Wang, C., & Wang, J. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.07.104 · Cited by 38
Rosello, A. P., Silva, R., Benítez, C. C., Bardallo, R. G., Calvo, M., Folch‐Puy, E., Carbonell, T., Palmeira, C. M., Roselló‐Catafau, J., & Adam, R. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165703 · Cited by 38
Vascular and Cardiac Oxidative Stress and Inflammation as Targets for Cardioprotection
Daiber, A., Steven, S., Euler, G., & Schulz, R. (2021) · Current Pharmaceutical Design · doi:10.2174/1381612827666210125155821 · Cited by 40
The Growing Landscape of Succinylation Links Metabolism and Heart Disease
Yang, L., Miao, S., Zhang, J., Wang, P., Liu, G., & Wang, J. (2021) · Epigenomics · doi:10.2217/epi-2020-0273 · Cited by 39
Szekeres, F. L. M., Walum, E., Wikström, P., & Arner, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-91575-8 · Cited by 40
Lerink, L. J. S., de Kok, M. J. C., Mulvey, J. F., Dévédec, S. E. L., Markovski, A. A., Wüst, R. C. I., Alwayn, I. P. J., Ploeg, R. J., Schaapherder, A. F., Bakker, J. A., et al. (2021) · American Journal of Transplantation · doi:10.1111/ajt.16868 · Cited by 38
The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn’s Disease
Monfort-Ferré, D., Caro, A., Menacho, M., Martí, M., Espina, B., Boronat-Toscano, A., Nuñez-Roa, C., Seco, J., Bautista, M., Espín, E., et al. (2022) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjac069 · Cited by 38
Lindsay, D. P., Camara, A. K. S., Stowe, D. F., Lubbe, R., & Aldakkak, M. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00058 · Cited by 38
“Studies have shown that selective accumulation of succinate is a universal metabolic signature of ischemia in the heart and is responsible for mitochondrial ROS production during reperfusion (Lukyanova, 2013; Chouchani et al., 2014).”
BackgroundInfluentialXiao, N., Yang, L., Yang, Y., Liu, L., Li, J., Liu, B., Liu, K., Qi, L., & Li, P. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00043 · Cited by 38
“As an inhibitor of malate/aspartate shuttle, AOA inhibited SDH activity (Figure 4E), indicating that malate/aspartate shuttle inhibition blocked the supply of fumarate for succinate formation (Chouchani et al., 2014).”
BackgroundInfluentialThe neuroprotective mechanism of lithium after ischaemic stroke
Chen, B., Zhang, M., Ji, M., Zhang, D., Chen, B., Gong, W., Li, X., Zhou, Y., Dong, C., Wen, G., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03051-2 · Cited by 37
Yakupova, E. I., Maleev, G. V., Krivtsov, A. V., & Plotnikov, E. Y. (2022) · Experimental Biology and Medicine · doi:10.1177/15353702221080130 · Cited by 39
Lu, Y., Chen, K., Zhao, W., Hua, Y., Bao, S., Zhang, J., Wu, T., Ge, G., Yu, Y., Sun, J., et al. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-02189-3 · Cited by 37
“Another study found that the abnormal accumulation of succinate leads to the excessive mitochondrial reactive oxygen species (mtROS) production in the case of I/R injury [25].”
BackgroundProtective Mechanisms of Hypothermia in Liver Surgery and Transplantation
Olthof, P. B., Reiniers, M. J., Dirkes, M. C., van Gulik, T. M., Heger, M., & van Golen, R. F. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00158 · Cited by 41
Measurement of metabolic fluxes using stable isotope tracers in whole animals and human patients
Reisz, J. A., & D’Alessandro, A. (2017) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000393 · Cited by 37
Huang, Y. X. R., Ma, T., Ye, Z., Li, H., Zhao, Y., Chen, W., Fu, Y., Ye, Z., Sun, A., & Li, Z. (2017) · Experimental Eye Research · doi:10.1016/j.exer.2017.08.016 · Cited by 37
“SOD is also an important enzyme that protects lenses and LECs from oxidative damage by preventing the production of superoxide in mitochondria (Reddy et al., 2004).”
BackgroundInfluentialKomlódi, T., Geibl, F. F., Sassani, M., Ambrus, A., & Tretter, L. (2018) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-018-9766-8 · Cited by 36
Yang, Y., Yan, X., Xue, J., Zheng, Y., Chen, M., Sun, Z., Liu, T., Wang, C., You, H., & Luo, D. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0277-x · Cited by 37
Reactive Oxygen Species Related Noncoding RNAs as Regulators of Cardiovascular Diseases
Dong, Y., Xu, W., Liu, C., Liu, P., Li, P., & Wang, K. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.30464 · Cited by 38
“During ischemia, the respiratory chain becomes reduced along with the accumulation of the citric acid cycle intermediate succinate [31-33].”
BackgroundCardiac Proteome Profiling in Ischemic and Dilated Cardiomyopathy Mouse Models
Lu, D., Xia, Y., Chen, Z., Chen, A., Wu, Y., Jia, J., Sun, A., Zou, Y., Qian, J., & Ge, J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00750 · Cited by 36
“Ischemia-reperfusion initiates oxidative damage, cell death and aberrant immune responses through the production of mitochondrial ROS in the heart (Chouchani et al., 2014).”
BackgroundPlecitá‐Hlavatá, L., Engstová, H., Holendová, B., Tauber, J. A., Špaček, T., Petrásková, L., Křen, V., Špačková, J., Gotvaldová, K., Ježek, J., et al. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7800 · Cited by 37
“Superoxide production also diminishes/rises on the acceleration/retardation of cytochrome c shuttling, respectively (the latter independently of Dp) (21, 29, 45, 50), and it depends on ubiquinone homeostasis, or the rate of the reverse electron transport (8, 13, 65).”
BackgroundWeißenbacher, A., Huang, H., Surik, T., Faro, M. L. L., Ploeg, R. J., Coussios, C. C., Friend, P. J., & Kessler, B. M. (2020) · American Journal of Transplantation · doi:10.1111/ajt.16334 · Cited by 37
Reverse Electron Transfer by Respiratory Complex I Catalyzed in a Modular Proteoliposome System
Wright, J. J., Biner, O., Chung, I., Burger, N., Bridges, H. R., & Hirst, J. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c00274 · Cited by 37
Redox Modulation by Reversal of the Mitochondrial Nicotinamide Nucleotide Transhydrogenase
Murphy, M. P. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.012 · Cited by 37
“For example, a recent study to which I contributed suggested that complexes I and II may operate in reverse and contribute to ischemia-reperfusion injury (Chouchani et al., 2014).”
BackgroundInfluentialSelf-citationReprogramming of mitochondrial metabolism by innate immunity
Garaude, J. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.010 · Cited by 33
Pottecher, J., Adamopoulos, C., Lejay, A., Bouitbir, J., Charles, A.-L., Meyer, A., Singer, M., Wolff, V., Diemunsch, P., Laverny, G., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00579 · Cited by 33
“In turn, dysfunctional mitochondria increase ROS production in a vicious cycle (Zorov et al., 2006; Chouchani et al., 2014).”
BackgroundPang, P., Si, W., Wu, H., Ju, J., Liu, K., Wang, C., Jia, Y., Diao, H., Zeng, L.-H., Jiang, W., et al. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0291 · Cited by 37
“C ardiovascular diseases threaten human life and significantly influence global health load (Chouchani et al., 2014).”
Chen, Q., Xu, Q., Zhu, H., Wang, J., Sun, N., Bian, H., Yu, H., & Lin, C. (2023) · Chinese Medicine · doi:10.1186/s13020-023-00859-w · Cited by 38
“Enhanced generation of oxygen radicals and lipid per-oxidation can exacerbate myocardial damage [38].”
BackgroundAndreyev, A. Y., Yang, H., Doulias, P., Dolatabadi, N., Zhang, X., Luevanos, M., Blanco, M., Baal, C., Putra, I., Nakamura, T., et al. (2024) · Advanced Science · doi:10.1002/advs.202306469 · Cited by 35
Tricarboxylic Acid Cycle Intermediates and Individual Ageing
Kurhaluk, N. (2024) · Biomolecules · doi:10.3390/biom14030260 · Cited by 39
“One of the pharmacological ways to solve this problem is the use of SC, which has previously been shown to have a pronounced antihypoxic [154] and antioxidant effect, especially on ischaemia–reperfusion injury [123,155].”
BackgroundCardiac arrhythmogenesis: roles of ion channels and their functional modification
Lei, M., Salvage, S. C., Jackson, A. P., & Huang, C. L.-H. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1342761 · Cited by 41
“…insulin resistance and type 2 diabetic conditions (Vianna et al., 2006; Sato et al., 2009; Kucharska-Newton et al., 2010), and cardiac failure, accompanying primary hypertrophic or fi brotic changes (Terentyev et al., 2008; Grivennikova et al., 2010; Belevych et al., 2012; Chouchani et al., 2014).”
BackgroundWang, X., Li, M., Wang, F., Mao, G.-H., Wu, J., Han, R., Sheng, R., Qin, Z., & Ni, H. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.03.011 · Cited by 36
Pattern-Recognition Receptors and Immunometabolic Reprogramming: What We Know and What to Explore
Kumar, V., & Stewart, J. H. (2024) · Journal of Innate Immunity · doi:10.1159/000539278 · Cited by 39
“…hard to ef fi ciently consumed by complex III, causing reverse electron transport (RET, where electron transfer occurs in the reverse direction from CoQH 2 to ubiquinone or CoQ) at complex I and increasing mtROS production, which further supports HIF-1 α stabilization and IL-1 β synthesis [75, 76].”
BackgroundAdvances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion
Ao-Di, F., Han-Qing, L., Xi-Zheng, W., Yang, K., Hong-Xin, G., Hai-xia, Z., Guan-Wei, F., & Li-Lan (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111370 · Cited by 38
Barnett, D., Zimmer, T. S., Booraem, C., Palaguachi, F., Meadows, S. M., Xiao, H., Wong, M. Y., Luo, W., Gan, L., Chouchani, E. T., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01390-y · Cited by 41
Self-citationLu, L., Guo, L., Gauba, E., Tian, J., Wang, L., Tandon, N., Shankar, M., Beck, S. J., Du, Y., & Du, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144068 · Cited by 37
Pyridine Dinucleotides from Molecules to Man
Fessel, J. P., & Oldham, W. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7120 · Cited by 35
“This would not only limit ROS production by NADPH oxidases, it would also increase the availability of NADPH for channeling into antioxidant defense mechanisms to offset ROS produced by other routes during ischemia/reperfusion, such as reverse electron transfer being driven by succinate accumulation in mitochondria (3…”
DeBerge, M., Zhang, S., Glinton, K. E., Grigoryeva, L., Hussein, I., Vorovich, E., Ho, K. J., Luo, X., & Thorp, E. B. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01428 · Cited by 40
“The increase in succinate stabilizes hypoxia inducible factor (HIF)-1α resulting in an increase in reverse electron transport and ROS production from complex I of the electron transport chain and favoring glycolysis by promoting phosphofructokinase isoform conversion (135, 138).”
BackgroundPushing the Limits: Machine Preservation of the Liver as a Tool to Recondition High-Risk Grafts
BOTEON, Y. L., Afford, S. C., & Mergental, H. (2018) · Current Transplantation Reports · doi:10.1007/s40472-018-0188-7 · Cited by 36
Locci, E., Noto, A., Puddu, M., Pomero, G., Demontis, R., Dalmazzo, C., Delogu, A., Fanos, V., d’Aloja, E., & Gancia, P. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194267 · Cited by 36
She, L., Xu, D., Wang, Z., Zhang, Y., Wei, Q., Aa, J., Wang, G., Liu, B., & Xie, Y. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.05.002 · Cited by 37
Liu, Y., Paterson, M. R., Baumgardt, S. L., Irwin, M. G., Xia, Z., Bosnjak, Z. J., & Ge, Z. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy157 · Cited by 36
“It has been known that in response to ischaemia and reperfusion, either ECs or CMs produce and release multiple endogenous mediators such as NO, reactive oxygen species, adenosine, cyclic ADP-ribose, opioids, neuregulin, and succinate.(22,24,32,33) These mediators possess strong biological effects on adjacent cells an…”
BackgroundZhao, Y.-P., Wang, F., Jiang, W., Liu, J., Liu, B., Qi, L., & Zhou, W. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2019.1566338 · Cited by 36
“Moreover, in recent years, it has been deeply studied that myocardial I/R injury is closely related to the activation of succinate dehydrogenase (SDH) located in mitochondrial membrane [14].”
BackgroundColmenero, F. (2020) · Materials Advances · doi:10.1039/d0ma00019a · Cited by 36
Non-invasive biomarkers for monitoring the immunotherapeutic response to cancer
Nisar, S., Bhat, A. A., Hashem, S., Yadav, S. K., Rizwan, A., Singh, M. K., Bagga, P., Macha, M. A., Frenneaux, M. P., Reddy, R. D., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02656-7 · Cited by 38
DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury
Lazzari, F. D., Prag, H. A., Gruszczyk, A. V., Whitworth, A. J., & Bisaglia, M. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101884 · Cited by 36
“Succinate is thought to arise due to the reversal activity of complex II, converting fumarate to succinate, though there may also be a contribution from the canonical Krebs cycle supported by glutaminolysis [66 – 68].”
Cellular crosstalk in cardioprotection: Where and when do reactive oxygen species play a role?
Martins‐Marques, T., Rodríguez‐Sinovas, A., & Girão, H. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.044 · Cited by 38
Dahl, H.-A., Johansen, A., Nilsson, G., & Lefevre, S. (2021) · Metabolites · doi:10.3390/metabo11070435 · Cited by 36
“Taking into account the greatly elevated liver and plasma levels of succinate in crucian carp during anoxia, we speculate if succinate is transported to the liver to limit the production of ROS during reoxygenation in other tissues.”
BackgroundInfluentialNew insights into survival strategies to oxygen deprivation in anoxia‐tolerant vertebrates
Fago, A. (2022) · Acta Physiologica · doi:10.1111/apha.13841 · Cited by 38
Small molecules as modulators of regulated cell death against ischemia/reperfusion injury
Chen, D., Guo, Y. P., Li, X., Zhang, G., & Li, P. (2022) · Medicinal Research Reviews · doi:10.1002/med.21917 · Cited by 38
Yan, X., He, M., Huang, H., Wang, Q., Hu, Y., Wang, X., Jin, M., Wang, Y., Xia, Y., Li, Y., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102442 · Cited by 37
RetractedRauckhorst, A. J., Borcherding, N. C., Pape, D., Kraus, A. S., Scerbo, D., & Taylor, E. B. (2022) · bioRxiv · doi:10.1016/j.molmet.2022.101596 · Cited by 31
Regulation of endogenous cardiomyocyte proliferation: The known unknowns
Secco, I., & Giacca, M. (2023) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2023.04.001 · Cited by 35
Stimulator of interferon genes (STING): Key therapeutic targets in ischemia/reperfusion injury
Lv, J., Xuanxuan, Z., Xing, C., Chen, Y., Bian, H., Yin, H., Gu, X., & Su, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115458 · Cited by 36
Multi‐omic analyses and network biology in cardiovascular disease
Reitz, C. J., Kuzmanov, U., & Gramolini, A. O. (2023) · PROTEOMICS · doi:10.1002/pmic.202200289 · Cited by 35
Wisel, S. A., Steggerda, J. A., & Kim, I. K. (2024) · Transplantation Direct · doi:10.1097/txd.0000000000001726 · Cited by 35
CoQ imbalance drives reverse electron transport to disrupt liver metabolism
Goncalves, R. L. S., Wang, Z. B., Riveros, J. K., Parlakgül, G., Inouye, K., Lee, G. Y., Fu, X., Saksi, J., Rosique, C., Hui, S. T., et al. (2025) · Nature · doi:10.1038/s41586-025-09072-1 · Cited by 39
“Succinate in particular has been shown to promote RET in other contexts 18,19,24 (Extended Data Fig.”
Succinate in innate immunity: linking metabolic reprogramming to immune modulation
Atallah, R., Gindlhuber, J., & Heinemann, Á. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1661948 · Cited by 41
“Upon reperfusion, metabolism of succinate via SDH is responsible for mitochondrial ROS production through reverse electron transport at complex I (53).”
Guide to the Pharmacology of Mitochondrial Potassium Channels
Augustynek, B., Kunz, W. S., & Szewczyk, A. M. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_79 · Cited by 37
Ferguson, D. C. J., Smerdon, G. R., Harries, L. W., Dodd, N. J. F., Murphy, M. P., Curnow, A., & Winyard, P. G. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.08.025 · Cited by 35
Self-citationBundgaard, A., Qvortrup, K., Rasmussen, L. J., & Fago, A. (2019) · Journal of Experimental Biology · doi:10.1242/jeb.200410 · Cited by 35
Singh‐Mallah, G., Nair, S., Sandberg, M., Mallard, C. E., & Hagberg, H. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7779 · Cited by 35
“This rapid oxidation drives reverse electron transport (RET) at C-I, in which electrons are forced from reduced coenzyme Q (CoQ) in C-II back to C-I, generating large amounts of O 2 (cid:2) - (39).”
Manhas, N., Duong, Q. V., Lee, P., Richardson, J. D., Robertson, J. D., Moxley, M. A., & Bazil, J. N. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014483 · Cited by 36
Liu, W., Liu, Y., Pan, Z., Zhang, X., Qin, Y., Chen, X., Li, M., Chen, X., Zheng, Q., Liu, X., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.568116 · Cited by 35
“For instance, a previous study showed that the metabolic responses during myocardial ischemic injury lead to an increase in the mitochondrial citric acid cycle intermediate succinate (Chouchani et al., 2014).”
BackgroundMetabolomics and metabolites in ischemic stroke
Chumachenko, M. S., Waseem, T. V., & Fedorovich, S. V. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2021-0048 · Cited by 35
Post-translational Acetylation Control of Cardiac Energy Metabolism
Ketema, E. B., & Lopaschuk, G. D. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.723996 · Cited by 37
“In a separate study, accumulation of succinate during ischemia and its rapid oxidation by SDH during reperfusion can drive extensive ROS generation in a murine I/R injury model (228).”
BackgroundKotla, S., Zhang, A., Imanishi, M., Ko, K. A., Lin, S. H., Gi, Y. J., Moczygemba, M. M., Isgandarova, S., Schadler, K., Chung, C. D., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102132 · Cited by 36
Self-citationTomar, N., Zhang, X., Kandel, S. M., Sadri, S., Yang, C., Liang, M., Audi, S. H., Cowley, A. W., & Dash, R. K. (2021) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2021.148518 · Cited by 34
Khellaf, A., García, N. M., Tajsic, T., Alam, A., Stovell, M. G., Killen, M. J., Howe, D. J., Guilfoyle, M. R., Jalloh, I., Timofeev, I. S., et al. (2021) · Apollo (University of Cambridge) · doi:10.17863/cam.79807 · Cited by 35
Self-citationKoenitzer, J. R., Bonacci, G., Woodcock, S. R., Chen, C.-S., Cantú‐Medellín, N., Kelley, E. E., & Schopfer, F. J. (2015) · Redox Biology · doi:10.1016/j.redox.2015.11.002 · Cited by 37
“This injury is inhibited by the prodrug dimethylmalonate, which is converted to the flavin-binding complex II inhibitor malonate, and a similar mechanism is possible with OA-NO2 through specific binding to the flavin-containing Fp subunit [43,44].”
BackgroundBrandes, R. P., Rezende, F., & Schröder, K. (2018) · Circulation Research · doi:10.1161/circresaha.118.313146 · Cited by 35
Hu, Y., Tian, X., Zhao, Y., Wang, Z., Lin, M., Sun, R., Wang, Y., Wang, Z., Li, G., Zheng, S., et al. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0137 · Cited by 34
“S5), which subsequently causes massive mitochondrial ROS formation in the reperfusion phase due to reverse electron transport (Chouchani et al., 2014).”
Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease
Balderas, E., Lee, S., Rai, N. K., Mollinedo, D. M., Duron, H. E., & Chaudhuri, D. (2024) · Physiology · doi:10.1152/physiol.00014.2024 · Cited by 36
Environmental impacts of polymeric flame retardant breakdown
Liu, X., Xiong, Y., Gou, X., Zhao, L. Q., Wang, S., Wei, Y., Fan, X., Yang, Y., Blum, A., Jahl, L. G., et al. (2025) · Nature Sustainability · doi:10.1038/s41893-025-01513-z · Cited by 36
“Evidence from mouse studies also indicates that mitochondrial dysfunction could affect ocular and brain development, cause cardiovascular injury and affect motor behaviours 39–41 .”
García‐Giménez, J. L., Cánovas‐Cervera, I., Nácher-Sendra, E., Dolz-Andrés, E., Sánchez-Bernabéu, Á., Agúndez, A. B., Hernández‐Gil, J., Mena, S., & Pallardó, F. V. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.04.004 · Cited by 36
Varvarousis, D., Xanthos, T. T., Ferino, G., Noto, A., Iacovidou, N. M., Mura, M., Scano, P., Chalkias, A. F., Papalois, A. E., De‐Giorgio, F., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16857-6 · Cited by 34
Metadata
- Authors
- Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijević, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N. J., Smith, A. C., Eyassu, F., Shirley, R., Hu, C.-H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S. H., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., & Murphy, M. P.
- Affiliations
- University of Cambridge (GB)
- St Thomas' Hospital (GB)
- University College London (GB)
- MRC Mitochondrial Biology Unit (GB)
- University of Rochester Medicine (US)
- University of Glasgow (GB)
- Corresponding author
- Frezza, Christian
- Krieg, Thomas
- Murphy, Michael P.
- ORCID
- Chouchani, Edward T.
- Gaude, Edoardo
- Aksentijević, Dunja
- Logan, Angela
- Nadtochiy, Sergiy M.
- Ord, Emily N. J.
- Smith, Anthony C.
- Dare, Anna J.
- James, Andrew M.
- Rogatti, Sebastian
- Hartley, Richard C.
- Eaton, Simon
- Costa, Ana S. H.
- Brookes, Paul S.
- Davidson, Sean M.
- Duchen, Michael R.
- Shattock, Michael J.
- Robinson, Alan J.
- Work, Lorraine M.
- Frezza, Christian
- Krieg, Thomas
- Murphy, Michael P.
- Venue
- Nature
- Published
- 2014-11-05
- Volume
- 515
- Issue
- 7527
- Pages
- 431-435
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4255242
- OpenAlex
- W2122091775
- Cited by
- 2,907
- References
- 53
- Citations by year
- 2026: 325 · 2025: 291 · 2024: 295 · 2023: 287 · 2022: 318 · 2021: 308 · 2020: 256 · 2019: 240 · 2018: 196 · 2017: 152 · 2016: 154 · 2015: 74 · 2014: 6
- FWCI
- 94.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Apollo
- Funders
- British Heart Foundation (RG/12/4/29426, PG/07/126/24223, PG/12/42/29655)
- Canadian Institutes of Health Research
- Medical Research Council (MC_UU_12022/6)
- Biotechnology and Biological Sciences Research Council (BB/I012923/1)
- National Heart, Lung, and Blood Institute (R01HL071158)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Keywords
- ischemia-reperfusion injury, mitochondrial reactive oxygen species, reverse electron transfer, mitochondrial complex I, malate-aspartate shuttle, TCA cycle, myocardial infarction, stroke, succinate dehydrogenase inhibition
- MeSH terms
- Adenosine Monophosphate, Animals, Aspartic Acid, Citric Acid Cycle, Disease Models, Animal, Electron Transport, Fumarates, Ischemia, Malates, Male, Mitochondria, Myocardial Infarction, Myocardium, NAD, Succinate Dehydrogenase, Reperfusion Injury, Reactive Oxygen Species, Succinic Acid, Stroke, Myocytes, Cardiac, Electron Transport Complex I, Mice, Metabolomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
