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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.
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“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]
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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
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–500 of 1,003
Molecular mechanisms of oxidative stress in stroke and cancer
Chavda, V. K., Chaurasia, B. K., Garg, K., Deora, H., Umana, G. E., Palmisciano, P., Scalia, G., & Lu, B. (2021) · Brain Disorders · doi:10.1016/j.dscb.2021.100029 · Cited by 98
Machine perfusion of the liver: applications in transplantation and beyond
Ceresa, C. D. L., Nasralla, D., Pollok, J., & Friend, P. J. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00557-8 · Cited by 92
Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation
Li, Y., Li, Y., Liu, X.-T., Zhang, L., Chen, Y.-H., Zhao, Q., Gao, W. Y., Liu, B., Yang, H. Q., & Li, P. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110391 · Cited by 88
Valls-Lacalle, L., Barba, I., Miró-Casas, E., Ruiz-Meana, M., Rodríguez-Sinovas, A., & García-Dorado, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-20866-4 · Cited by 88
Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury
Martin, J. L., Gruszczyk, A. V., Beach, T. E., Murphy, M. P., & Saeb‐Parsy, K. (2018) · Pediatric Nephrology · doi:10.1007/s00467-018-3984-5 · Cited by 88
“The recognition of a specific metabolic pathway that drives mitochondrial ROS production during IR injury opens up the possibility of a novel therapeutic strategy that acts upstream of ROS generation [15], namely competitive inhibition of succinate dehydrogenase, which has been shown to ameliorate IR injury in a varie…”
Self-citationReview of Current Machine Perfusion Therapeutics for Organ Preservation
Xu, J., Buchwald, J. E., & Martins, P. N. A. (2020) · Transplantation · doi:10.1097/tp.0000000000003295 · Cited by 88
“The complex process of IRI activates numerous genes that lead to cell apoptosis and tissue injury.(4) Therefore, gene-silencing agents such as siRNA and shRNA have been explored in solid organ transplantation to reduce graft injury.”
BackgroundCui, D., Kong, N., Ding, L., Guo, Y., Yang, W. R., & Yan, F. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202101215 · Cited by 90
Mitochondrial Sirtuins in cardiometabolic diseases
Tang, X., Chen, X., Chen, H., & Liu, D. (2017) · Clinical Science · doi:10.1042/cs20160685 · Cited by 87
Lautz, A. J., Morgan, R. W., Karlsson, M., Mavroudis, C. D., Ko, T. S., Licht, D. J., Nadkarni, V., Berg, R. A., Sutton, R. M., & Kilbaugh, T. J. (2019) · Critical Care Medicine · doi:10.1097/ccm.0000000000003620 · Cited by 87
Mitochondrial Complex I Inhibition by Metformin Limits Reperfusion Injury
Mohsin, A. A., Chen, Q., Quan, N., Rousselle, T. V., Maceyka, M. W., Samidurai, A., Thompson, J., Hu, Y., Li, J., & Lesnefsky, E. J. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.254300 · Cited by 87
Duan, C., Kuang, L., Xiang, X., Zhang, J., Zhu, Y., Wu, Y., Yan, Q., Liu, L., & Li, T. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2461-9 · Cited by 88
Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis
Chandra, P., He, L., Zimmerman, M. D., Yang, G., Köster, S., Ouimet, M. I., Wang, H., Moore, K. J., Dartois, V. A., Schilling, J. D., et al. (2020) · mBio · doi:10.1128/mbio.01139-20 · Cited by 88
“body (59), ischemia-reperfusion injury (60), and extending fly life span (61).”
BackgroundWang, T., Liu, J., Luo, X., Hu, L., & Lu, H. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107824 · Cited by 88
Wijnker, P. J. M., Sequeira, V., Kuster, D. W. D., & van der Velden, J. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7236 · Cited by 90
Zhang, M. Y., Dugbartey, G. J., Juriasingani, S., & Şener, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126452 · Cited by 88
Du, J., Yin, G., Hu, Y., Shi, S., Jiang, J., Song, X., Zhang, Z., Wei, Z., Tang, C., & Lyu, H. (2020) · Aging · doi:10.18632/aging.202194 · Cited by 85
“Although ROS at moderate concentrations are important for physiological processes, excessive ROS generation and antioxidant consumption contribute to secondary brain injury [33].”
BackgroundWang, Y., Wu, J., Wang, J., He, L., Lai, H., Zhang, T., Wang, X., & Li, W. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.01.007 · Cited by 86
Multifaceted mitochondria in innate immunity
Marques, E., Kramer, R., & Ryan, D. G. (2024) · npj Metabolic Health and Disease · doi:10.1038/s44324-024-00008-3 · Cited by 91
Ovarian aging: energy metabolism of oocytes
Bao, S., Yin, T., & Liu, S. (2024) · Journal of Ovarian Research · doi:10.1186/s13048-024-01427-y · Cited by 92
Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment?
Bar‐Or, D., Carrick, M. M., Mains, C. W., Rael, L. T., Slone, D. S., & Brody, E. N. (2015) · Redox Report · doi:10.1179/1351000215y.0000000005 · Cited by 87
Kaludercic, N., & Giorgio, V. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3869610 · Cited by 91
“Administration of MitoSNO within the first minutes of reperfusion temporarily inhibits complex I and thus blocks the reverse electron flow that leads to generation of ROS, oxidative damage, and tissue necrosis [74, 75].”
BackgroundHuang, S., Braun, H., Gawryluk, R. M. R., & Millar, A. H. (2019) · The Plant Journal · doi:10.1111/tpj.14227 · Cited by 84
Florido, J., Martínez-Ruiz, L., Rodríguez-Santana, C., López‐Rodríguez, A., Hidalgo‐Gutiérrez, A., Cottet‐Rousselle, C., Lamarche, F., Schlattner, U., Guerra‐Librero, A., Aranda‐Martínez, P., et al. (2022) · Journal of Pineal Research · doi:10.1111/jpi.12824 · Cited by 89
“However, under specific conditions such as hypoxia, complex II subunits can lead to increased ROS generation via RET.(18,28) One way to differentiate RET‐ROS production is by using rotenone, which increases ROS production in the FIGURE 5 Melatonin‐induced oncostatic effects are inhibited in Cal‐27 expressing AOX in vi…”
BackgroundNarne, P., Pandey, V., & Phanithi, P. B. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.05.008 · Cited by 84
New and revisited approaches to preserving the reperfused myocardium
Kloner, R. A., Brown, D. A., CSETE, M. E., Dai, W., Downey, J. M., Gottlieb, R. A., Hale, S. L., & Shi, J. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.102 · Cited by 86
Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems
Abe, N., Nishihara, T., Yorozuya, T., & Tanaka, J. (2020) · Cells · doi:10.3390/cells9092132 · Cited by 88
“However, more than 90% of the ROS produced by cells originate from mitochondria (MitoROS) [68], which are thought to be the main cause of the oxidative damage that occurs during brain injury [69,70].”
BackgroundOh, C. J., Kim, M., Lee, J.-M., Kim, D. H., Kim, I., Park, S., Kim, Y., Lee, K., Lee, S., Lim, C. W., et al. (2023) · Kidney International · doi:10.1016/j.kint.2023.06.022 · Cited by 84
Mitochondrial Dysfunction in Cardiovascular Diseases
Yang, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051917 · Cited by 91
“Similarly, in ischemic heart disease, mitochondrial dysfunction exacerbates ischemia–reperfusion injury, leading to cell death and tissue damage [6,7].”
Mitochondria “THE” target of myocardial conditioning
Boengler, K., Lochnit, G., & Schulz, R. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00124.2018 · Cited by 82
Bundgaard, A., James, A. M., Gruszczyk, A. V., Martin, J. L., Murphy, M. P., & Fago, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-39836-5 · Cited by 80
Self-citationOsuna‐Prieto, F. J., Martínez‐Téllez, B., Ortiz-Alvarez, L., Di, X., Jurado‐Fasoli, L., Xu, H., Ceperuelo‐Mallafré, V., Núñez‐Roa, C., Köhler, I., Segura‐Carretero, A., et al. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01333-3 · Cited by 81
Free radicals: Relationship to Human Diseases and Potential Therapeutic applications
Zarić, B. L., Mačvanin, M., & Isenović, E. R. (2022) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2022.106346 · Cited by 105
Research progress on post-translational modification of proteins and cardiovascular diseases
Cheng, X., Wang, K., Zhao, Y., & Wang, K. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01560-5 · Cited by 86
“Pretreatment of SIRT5 knockout mouse hearts with succinate dehydrogenase competitive inhibitors reduced I/R injury, suggesting that alterations in succinate dehydrogenase activity have a definite effect on I/R injury and that succinate modification may play an important role in I/R injury [67].”
BackgroundMitochondrial heterogeneity in diseases
Chen, L., Zhou, M., Li, H., Liu, D., Liao, P., Yao, Z., Zhang, C., Zou, W., & Gao, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01546-w · Cited by 88
“Dimethyl malonate (DMM), inhibitor of SDH, has been decreased succinate accumulation and oxidation during heart ischemia and reperfusion (IR).(360) Further study has observed DMM to inhibit LPS-induced mtROS generation in inflammatory macrophage and to promote an antiinflammatory outcome.”
BackgroundFatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes
Dodd, M. S., Fialho, M. D. L. S., Aparicio, C. N. M., Kerr, M. J., Timm, K. N., Griffin, J. L., Luiken, J. J. F. P., Glatz, J. F. C., Tyler, D. J., & Heather, L. C. (2018) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2018.04.005 · Cited by 81
“Succinate could be derived from the malateaspartate shuttle utilizing glycolytic NADH, coupled to reverse Krebs cycle and succinate dehydrogenase activity (31).”
BackgroundInfluentialKohlhauer, M., Pell, V. R., Burger, N., Spiroski, A., Gruszczyk, A. V., Mulvey, J. F., Mottahedin, A., Costa, A. S. H., Frezza, C., Ghaleh, B., et al. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0727-0 · Cited by 81
Self-citationFock, E. M., & Parnova, R. G. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020144 · Cited by 85
“An increase in the succinate level arises from SDH, operating in its opposite direction, which, in turn, is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle [182].”
BackgroundMitochondria and ischemia reperfusion injury
Panconesi, R., Widmer, J. D., Carvalho, M. F., Eden, J., Dondossola, D. E., Dutkowski, P., & Schlegel, A. A. (2022) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000001015 · Cited by 81
Zhang, W., & Lang, R. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1266973 · Cited by 88
Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation
Bazil, J. N., Beard, D. A., & Vinnakota, K. C. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.036 · Cited by 81
Mansor, L. S., Fialho, M. D. L. S., Yea, G., Coumans, W. A., West, J. A., Kerr, M. J., Carr, C. A., Luiken, J. J. F. P., Glatz, J. F. C., Evans, R. D., et al. (2017) · Cardiovascular Research · doi:10.1093/cvr/cvx045 · Cited by 80
Herr, D. J., Baarine, M., Aune, S. E., Li, X., Ball, L. E., Lemasters, J. J., Beeson, C., Chou, C. J., & Menick, D. R. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.12.004 · Cited by 78
“Recent work has shown that inhibiting fatty acid oxidation protects the heart from injury [56], as does inhibition of the malate aspartate shuttle [57], while metabolic succinate accumulation [43] sensitizes the heart to injury.”
BackgroundWang, Y., Lilienfeldt, N., & Hekimi, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00040.2023 · Cited by 88
Zhang, Z., Yang, W., Wang, L., Zhu, C., Cui, S., Wang, T., Gu, X., Liu, Y., & Qiu, P. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03285-3 · Cited by 85
“The inhibition of complex I activity by vol - atile anesthetics reduces the reverse electron transport and the subsequent generation of large amounts of ROS driven by mitochondria during myocardial and cerebral ischemia–reperfusion [75, 77].”
BackgroundRoy, B. (2025) · Medical Sciences · doi:10.3390/medsci13030087 · Cited by 103
Plasma succinate is a predictor of mortality in critically injured patients
D’Alessandro, A., Moore, H. B., Moore, E. E., Reisz, J. A., Wither, M. J., Ghasasbyan, A., Chandler, J. G., Silliman, C. C., Hansen, K. C., & Banerjee, A. M. (2017) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000001565 · Cited by 80
mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling
Hämäläinen, R. H., Ahlqvist, K. J., Ellonen, P., Lepistö, M., Logan, A., Otonkoski, T., Murphy, M. P., & Suomalainen, A. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.05.009 · Cited by 79
“This downregulation of mitochondrial ATP production may leave the mitochondria under conditions of high proton-motive force and a reduced respiratory chain (RC), which favors mitochondrial reactive oxygen species (ROS) production (Chouchani et al., 2014; Murphy, 2009).”
BackgroundSelf-citationHypothermic Machine Preservation of the Liver: State of the Art
Schlegel, A. A., Muller, X., & Dutkowski, P. (2018) · Current Transplantation Reports · doi:10.1007/s40472-018-0183-z · Cited by 80
Dikalov, S., & Dikalova, A. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7632 · Cited by 79
“Production of mitochondrial superoxide via reverse electron transport (RET) is of particular importance in vascular and cardiac oxidative stress (20, 84).”
BackgroundNeurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons
Meng, X., Song, Q., Liu, Z., Liu, X., Wang, Y., & Liu, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1400544 · Cited by 84
“Decreased activity of SDH leads to the accumulation of succinate, which is rapidly oxidized, driving ROS generation through reverse electron transfer to complex I, resulting in PANoptosis in cells (Chouchani et al., 2014; Shi et al., 2023b).”
BackgroundRedox regulation of UPR signalling and mitochondrial ER contact sites
Casas-Martinez, J. C., Samali, A., & McDonagh, B. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05286-0 · Cited by 85
“ROS generation during reverse electron transport has been identified as a major cause of oxidative damage in conditions such as ischaemia where there is an accumulation of succinate [153].”
BackgroundInnate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis
Wang, Y., Lu, J., Carisey, A. F., Chadchan, S. B., Lee, H. W., Malireddi, R. K. S., Sharma, B. R., Nagakannan, P., Tweedell, R. E., Palacios, G., et al. (2025) · Cell · doi:10.1016/j.cell.2025.11.002 · Cited by 93
Self-citationEstablishment of local searching methods for orbitrap-based high throughput metabolomics analysis
Tang, H., Wang, X., Xu, L., Ran, X., Li, X., Chen, L., Zhao, X., Deng, H., & Liu, X. (2016) · Talanta · doi:10.1016/j.talanta.2016.04.051 · Cited by 79
O’Brien, M., Chalker, J., Slade, L., Gardiner, D., & Mailloux, R. J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.02.046 · Cited by 82
Bouhamida, E., Morciano, G., Perrone, M., Kahsay, A. E., Della Sala, M., Wieckowski, M. R., Fiorica, F., Pinton, P., Giorgi, C., & Patergnani, S. (2022) · Biology · doi:10.3390/biology11020300 · Cited by 87
The complex interplay between kidney injury and inflammation
McWilliam, S. J., Wright, R. D., Welsh, G. I., Tuffin, J. P., Budge, K., Swan, L. E., Wilm, T. P., Martinas, I.-R., Littlewood, J., & Oni, L. (2020) · Clinical Kidney Journal · doi:10.1093/ckj/sfaa164 · Cited by 79
“The metabolites of the citric acid cycle, required for aerobic respiration via electron transport, become depleted, except for succinate, which accumulates during ischaemia [38].”
BackgroundOu, W., Liang, Y., Yu, Q., Wu, W., Xie, M., Zhang, Y., Zhang, Y., Ji, L., Yu, H., & Li, T. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101994 · Cited by 78
“In support of it, the intensity of MitoSOX fluorescence, an indicator of mitochondrial ROS generation, was also attenuated by HA, companied by ameliorated post-H/R mitochondrial dysfunction and apoptosis (Fig.”
BackgroundInfluentialZou, J., Wang, J., Ye, W., Lü, J., Li, C., Zhang, D., Ye, W., Xu, S., Chen, C., Liu, P., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113626 · Cited by 80
Lochhead, J. J., Ronaldson, P. T., & Davis, T. P. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116186 · Cited by 84
Mailloux, R. J., Gardiner, D., & O’Brien, M. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.06.014 · Cited by 79
McManus, M. J., Picard, M. A., Chen, H.-W., de Haas, H. J., Potluri, P., Leipzig, J. N., Towheed, A., Angelin, A., Sengupta, P. P., Morrow, R. M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.002 · Cited by 84
“Second, the ND6P25L variant generates comparable total ROS production as Ant1 / and COIV421A, but the ND6P25L variant produces ROS only by FET, as opposed to both FET and RET for the Ant1 / and COIV421A variants.”
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Степанова, А., Sosunov, S. A., Niatsetskaya, Z. V., Konràd, C., Starkov, A. A., Manfredi, G., Wittig, I., Ten, V. S., & Galkin, A. S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7693 · Cited by 77
“the highest rate of H2O2 release in mitochondria, with complex I as the main site of ROS production (11, 12, 19, 39, 40, 47, 49, 51, 61, 63, 70, 71).”
BackgroundWarpsinski, G., Smith, M. J., Srivastava, S., Keeley, T. P., Siow, R. C. M., Fraser, P. A., & Mann, G. E. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101708 · Cited by 81
“Studies in vivo have reported that following ischemia-reperfusion injury in the heart and brain, accumulation of succinate in mitochondria drives reactive oxygen species generation via reverse electron transport at mitochondrial complex I, and that oxidative damage can be decreased by reducing succinate accumulation […”
BackgroundProgress in Stimuli‐Responsive Biomaterials for Treating Cardiovascular and Cerebrovascular Diseases
Tapeinos, C., Gao, H. J., Bauleth‐Ramos, T., & Santos, H. A. (2022) · Small · doi:10.1002/smll.202200291 · Cited by 79
Acute Kidney Injury by Ischemia/Reperfusion and Extracellular Vesicles
Nørgård, M. Ø., & Svenningsen, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015312 · Cited by 80
“The high succinate levels are problematic when the oxygen supply is reestablished by reperfusion in that this reverses the ETC’s electron transport and stimulates excessive mitochondria-derived ROS production [7,8].”
BackgroundInfluentialMolecular Mechanisms of Oxidative Stress in Acute Kidney Injury: Targeting the Loci by Resveratrol
Rashid, H., Jali, A. M., Akhter, M. S., & Abdi, S. A. H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010003 · Cited by 91
“It has been suggested by Chouchani et al., 2014, using comparative in vivo metabolomic analysis that characteristic metabolic pathways may be effective in mitochondria where O 2 •− is generated through reverse electron transport at complex I of the ETC [97].”
BackgroundRedox regulation of mitochondrial proteins and proteomes by cysteine thiol switches
Nietzel, T., Mostertz, J., Hochgräfe, F., & Schwarzländer, M. (2016) · Mitochondrion · doi:10.1016/j.mito.2016.07.010 · Cited by 75
Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury
Kulek, A. R., Anzell, A. R., Wider, J. M., Sanderson, T. H., & Przyklenk, K. (2020) · Cells · doi:10.3390/cells9010214 · Cited by 78
“Calcium overload activates proteases and phosphatases that modify components of the electron transport chain as well as key molecular GTPases involved in mitochondrial morphosis [99,165–168], effectively priming the ischemic myocardium for the hyperpolarization of mitochondrial membranes, burst of ROS production, disr…”
BackgroundCordes, T., & Metallo, C. M. (2021) · Metabolites · doi:10.3390/metabo11020117 · Cited by 75
“By exploiting the SDH inhibitory function of itaconate to limit damaging succinate accumulation [23,24], itaconate treatment allows mitochondria to gradually “awaken” and prevent cellular injury [22,25].”
BackgroundCardiac Troponins Metabolism: From Biochemical Mechanisms to Clinical Practice (Literature Review)
Chaulin, A. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222010928 · Cited by 63
Liu, G., Li, L., Huo, D., Li, Y., Wu, Y., Zeng, L., Cheng, P., Xing, M. M. Q., Zeng, W., & Zhu, C. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.03.001 · Cited by 75
Dengu, F., Abbas, S. H., Ebeling, G., & Nasralla, D. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9041046 · Cited by 75
“Ischaemia reperfusion injury (IRI) remains a necessary component of solid organ transplantation and involves a surge in pro-inflammatory cytokines such as interleukin-1 (IL-1) & interleukin-6 (IL-6), tumour necrosis factor (TNF-α), increased reactive oxygen species (ROS), neutrophil infiltration and complement activat…”
BackgroundN6-methyladenosine (m6A) methylation in ischemia–reperfusion injury
Yao, W., Han, X., Ge, M., Chen, C., Xiao, X., Li, H., & Hei, Z. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2686-7 · Cited by 77
Muller, X., Mohkam, K., Mueller, M., Schlegel, A. A., Dondero, F., Sepulveda, A., Savier, É., Scatton, O., Bucur, P. O., Salamé, E., et al. (2020) · Annals of Surgery · doi:10.1097/sla.0000000000004268 · Cited by 75
Myocardial‐Targeting Tannic Cerium Nanocatalyst Attenuates Ischemia/Reperfusion Injury
Wang, L., Qiu, S., Li, X., Zhang, Y., Huo, M., & Shi, J. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202305576 · Cited by 76
Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes
Moschandrea, C., Kondylis, V., Evangelakos, I., Herholz, M., Schneider, F., Schmidt, C., Yang, M. H., Ehret, S., Heine, M., Jaeckstein, M. Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06857-0 · Cited by 75
“The suppression of mitochondrial metabolism in Dars2 tamIEC-KO mice was corroborated by a reduction in aspartate 13,14 and an accumulation of succinate, which are hallmarks of OXPHOS dysfunction 15 (Extended Data Fig.”
Self-citationMetabolic reprogramming & inflammation: Fuelling the host response to pathogens
Gleeson, L. E., & Sheedy, F. J. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.10.007 · Cited by 78
Peruzzotti‐Jametti, L., & Pluchino, S. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.07.007 · Cited by 75
Hypothermic machine perfusion in liver transplantation
Schlegel, A. A., Kron, P., & Dutkowski, P. (2016) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000303 · Cited by 75
Turning the Oxygen Dial: Balancing the Highs and Lows
Baik, A. H., & Jain, I. H. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.04.005 · Cited by 70
The burgeoning field of innate immune‐mediated disease and autoinflammation
Peckham, D. G., Scambler, T., Savic, S., & McDermott, M. (2016) · The Journal of Pathology · doi:10.1002/path.4812 · Cited by 75
“An international panel of 22 experts was established to develop evidence-based recommendations for the management and treatment of CAPS, TRAPS and Mevalonate kinase deficiency (MKD) by using the European League Against Rheumatism standard operating procedures for developing best practice [154,155].”
BackgroundInfluentialEffects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile
Michaletti, A., Gioia, M., Tarantino, U., & Zolla, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-15612-1 · Cited by 73
Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack
Oates, J. R., McKell, M. C., Moreno‐Fernandez, M. E., Damen, M. S. M. A., Deepe, G. S., Qualls, J. E., & Divanovic, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02893 · Cited by 78
“During LPS stimulation, the breakdown of Sdh feeds electrons through complex I, known as reverse electron transport, resulting in mitochondrial ROS production (99).”
BackgroundThe Tricarboxylic Acid Cycle at the Crossroad Between Cancer and Immunity
Scagliola, A., Mainini, F., & Cardaci, S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7974 · Cited by 75
“Another lipophilic derivative with potent systemic anti-inflammatory activity is DMM, which is rapidly hydrolyzed within the cell to generate malonate and act as competitive inhibitor of SDH. DMM offered protection to ischemia– reperfusion (IR) injury (22).”
InfluentialTherapeutic Strategies for Regulating Mitochondrial Oxidative Stress
Yamada, Y., Takano, Y., Satrialdi, S., Abe, J., Hibino, M., & Harashima, H. (2020) · Biomolecules · doi:10.3390/biom10010083 · Cited by 76
“recently reported that a comparative in vivo metabolomic analysis could be used to identify the reverse electron transport of mitochondrial electron transport that is responsible for the massive generation of mitochondrial ROS that occurs as the result of IRI [92].”
BackgroundRole of Mitophagy in Cardiovascular Disease
Yang, Y., Li, T., Li, Z., Liu, N., Yan, Y., & Liu, B. (2020) · Aging and Disease · doi:10.14336/ad.2019.0518 · Cited by 74
Beach, T. E., Prag, H. A., Pala, L., Logan, A., Huang, M. M., Gruszczyk, A. V., Martin, J. L., Mahbubani, K. T. A., Hamed, M. O., Hosgood, S. A., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101640 · Cited by 73
“This is in contrast to previous studies in the rat brain [19] and mouse heart [30] although differences in compound administration, ischemia times and temperatures may also play a role.”
BackgroundResultSelf-citationChanges in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury
Bugarski, M., Ghazi, S., Polesel, M., Martins, J. R., & Hall, A. M. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020071003 · Cited by 72
The Unique Immunomodulatory Properties of MSC-Derived Exosomes in Organ Transplantation
Zheng, Q., Zhang, S., Guo, W.-Z., & Li, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.659621 · Cited by 76
“It also increases the chance of acute and chronic rejection of the transplanted organ and leads to late immunological inactivation (80).”
BackgroundRole of the MPTP in conditioning the heart – translatability and mechanism
Ong, S., Dongworth, R. K., Cabrera-Fuentes, H. A., & Hausenloy, D. J. (2014) · British Journal of Pharmacology · doi:10.1111/bph.13013 · Cited by 74
“More recently, Murphy’s group (Chouchani et al., 2014) has shown that ischaemia results in the myocardial accumulation of the mitochondrial complex II substrate, succinate, which at the onset of reperfusion then provides a substrate load to complex II, which via reverse electron transport feeding…”
Jiroutková, K., Krajčová, A., Žiak, J., Fric, M., Waldauf, P., Džupa, V., Gojda, J., Němcová‐Fürstová, V., Kovár̆, J., Elkalaf, M., et al. (2015) · Critical Care · doi:10.1186/s13054-015-1160-x · Cited by 76
“It has been recently shown that cells accumulate succinate during hypoxia [32–34] or inflammation [35].”
BackgroundZhang, J., Culp, M. L., Craver, J., & Darley-Usmar, V. M. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14308 · Cited by 74
Jin, H., Zhu, B., Liu, X., Jin, J., & Zou, H. (2019) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2019.06.013 · Cited by 73
Xue, J., Yan, X., Yang, Y., Chen, M., Wu, L., Gou, Z., Sun, Z., Talabieke, S., Zheng, Y., & Luo, D. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0748-8 · Cited by 73
Zeng, H., Wang, L., Zhang, J., Pan, T. S., Yu, Y., Lu, J., Zhou, P., Yang, H. Q., & Li, P. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.09.006 · Cited by 73
Sun, X., Gao, R., Li, W., Zhao, Y., Yang, H., Chen, H., Jiang, H., Dong, Z., Hu, J., Liu, J., et al. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.12.024 · Cited by 72
A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation
Kumar, R., Landry, A. P., Guha, A., Vitvitsky, V., Lee, H., Seike, K., Reddy, P. R., Lyssiotis, C. A., & Banerjee, R. V. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101435 · Cited by 74
“The known drivers of mitochondrial reverse electron transfer, which leads to reactive oxygen species (ROS) generation, are a high membrane potential and an overreduced CoQ pool (23).”
BackgroundInfluentialThe Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I
Padavannil, A., Ayala-Hernandez, M. G., Castellanos-Silva, E. A., & Letts, J. A. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.798353 · Cited by 69
“A heterozygous NDUFC2KO in rats causes an increase in ROS and mitochondrial dysfunction (Raffa et al., 2017).”
BackgroundInfluentialOsteometabolism: Metabolic Alterations in Bone Pathologies
Srivastava, R. K., Sapra, L., & Mishra, P. K. (2022) · Cells · doi:10.3390/cells11233943 · Cited by 79
“highlighted that accumulation of succinate occurs when there is an imbalance between the energy demand and the oxygen supply [94].”
BackgroundMitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?
Ciccarelli, G., Conte, S., Cimmino, G., Maiorano, P., Morrione, A., & Giordano, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021086 · Cited by 75
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
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