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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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“While metal ions possess exceptional antimicrobial properties, the excessive production of ROS during sterilization frequently damages adjacent healthy tissues [169].”
Immunometabolism in heart failure
Andreadou, I., Ghigo, A., Nikolaou, P., Świrski, F. K., Thackeray, J. T., Heusch, G., & Vilahur, G. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01165-8 · Cited by 76
“…heart owing to the reversal of the succinate dehydrogenase reaction, which results in the production of succinate from fumarate in cardiomyocytes 88 , and the release of succinate via MCT1 to the extracellular space by anoxic cardiomyocytes, probably because of its structural similarity to…”
Wahrnehmung der chemischen Prozesse in einzelnen Organellen mit niedermolekularen Fluoreszenzsonden
Xu, W., Zeng, Z., Jiang, J., Chang, Y., & Yuan, L. (2016) · Angewandte Chemie · doi:10.1002/ange.201510721 · Cited by 64
Mitochondrial Quality Control in Cardiac Diseases
Campos, J. C., Bozi, L. H. M., Bechara, L. R. G., Lima, V. M., & Ferreira, J. C. B. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00479 · Cited by 67
Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease
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“Upon oxidation of the excess succi- nate, the Cys39 can be reduced and complex I reactivated (Chouchani et al. 2014, 2016).”
BackgroundStructure and function of a novel antioxidant peptide from the skin of tropical frogs
Barbosa, É. A., Oliveira, A. L. S., Plácido, A., Socodato, R., Portugal, C. C., Mafud, A. C., Ombredane, A. S., Moreira, D. C., Vale, N., Bessa, L. J., et al. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.11.001 · Cited by 64
Cellular Compartmentation and the Redox/Nonredox Functions of NAD +
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“In the situation of reperfusion injury following tissue ischemia, a large burst of ROS generation occurs, and the primary source of these ROS is thought to be the reversal of electron transport through complex I, resulting in O2 - generation at the upstream FMN site (28).”
BackgroundSelf-citationMachine perfusion strategies in liver transplantation
Schlegel, A. A., Muller, X., & Dutkowski, P. (2019) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn.2019.04.04 · Cited by 64
“Upon normothermic liver reperfusion, accumulated electron donors, such as NADH and succinate, deliver high amounts of electrons to mitochondrial complex I and II, while ADP is not yet available for the ATP synthetase (complex V), due to previous nucleotide breakdown during ischemia (31,34).”
BackgroundJiang, M., Ni, J., Cao, Y., Xing, X., Wu, Q., & Fan, G. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9137654 · Cited by 68
“Via preconditioning with astragaloside IV, succinate was obviously increased and other related metabolites also recovered obviously, indicating that astragaloside IV probably prevented the production of excessive ROS.”
BackgroundInfluentialRewarming Injury after Cold Preservation
Minor, T., & von Horn, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092059 · Cited by 63
Circadian Regulation of Cardiac Physiology: Rhythms That Keep the Heart Beating
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A sensitive mass spectrometric assay for mitochondrial CoQ pool redox state in vivo
Burger, N., Logan, A., Prime, T. A., Mottahedin, A., Caldwell, S. T., Krieg, T., Hartley, R. C., James, A. M., & Murphy, M. P. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.11.028 · Cited by 60
Self-citationMitochondrial redox and TCA cycle metabolite signaling in the heart
Vujić, A., Koo, A., Prag, H. A., & Krieg, T. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.041 · Cited by 62
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“Myocardial ischaemia increases glutamate-derived conversion to α-ketoglutarate and succinate, preserving the NADH redox potential during anaerobic adaptations and cardiac remodelling 149,150 .”
Maintenance of Homeostasis in the Aging Hypothalamus: The Central and Peripheral Roles of Succinate
Chen, T. T., Maevsky, E. I., & Uchitel, M. L. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00007 · Cited by 62
“However, whether or not the same hypertensive effect can be reproduced in humans requires additional studies as many of the effects observed in isolated tissue preparation and in rodents have not been demonstrated in humans (117, 135).”
BackgroundHuang, Y., Zhou, J., Luo, S., Wang, Y., He, J., Luo, P., Chen, Z., Liu, T., Tan, X., Ou, J., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311909 · Cited by 63
Kôrge, P., John, S., Calmettes, G., & Weiss, J. N. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768325 · Cited by 63
“A recent metabolomics study demonstrated that succinate accumulation during ischemia correlated strongly with ROS production and injury during reperfusion (1).”
BackgroundInfluentialReceptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91
Trauelsen, M., Ulven, E. R., Hjorth, S. A., Brvar, M., Monaco, C. G., Frimurer, T. M., & Schwartz, T. W. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.09.005 · Cited by 63
“Inhibition of SDH activity and the associated accumulation of succinate is observed in response to ischemia [11], hypoxia [49], and hyperglycemia [15], and the accompanying GPR91-induced responses are linked with beneficial tissue adaptation to hypoxia/ischemia such as VEGF production in brain and retina [13,50], card…”
BackgroundMagnesium induces preconditioning of the neonatal brain via profound mitochondrial protection
Koning, G., Leverin, A., Nair, S., Schwendimann, L., Ek, C. J., Carlsson, Y., Gressèns, P., Thornton, C., Wang, X., Mallard, C. E., et al. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17746132 · Cited by 63
“The SDH inhibitor dimethyl malonate prevents accumulation of succinate and ROS, conferring significant neuroprotection.(53) Presently, we found that MgSO4 pre-treatment prevented the accumulation of succinate and improved mitochondrial function in the neonatal brain.”
BackgroundDunphy, B. J., Ruggiero, K., Zamora, L. N., & Ragg, N. L. C. (2018) · Journal of Thermal Biology · doi:10.1016/j.jtherbio.2018.03.006 · Cited by 64
Hill, B. G., Shiva, S., Ballinger, S. W., Zhang, J., & Darley-Usmar, V. M. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0268 · Cited by 66
“Early pioneer work has demonstrated a key role of mitochondrial complex II substrate, TCA cycle intermediate succinate, in reperfusion injury (Chouchani et al., 2014).”
BackgroundOxidative metabolism and efficiency: the delicate balancing act of mitochondria
Bottje, W. G. (2018) · Poultry Science · doi:10.3382/ps/pey405 · Cited by 71
Gao, J., Shao, K., Chen, X., Li, Z., Liu, Z., Yu, Z., Aung, L. H. H., Wang, Y., & Li, P. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.11.146 · Cited by 62
Ischemic Microenvironment‐Responsive Therapeutics for Cardiovascular Diseases
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Cardiac macrophages and emerging roles for their metabolism after myocardial infarction
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“Given that the majority of patients undergo a form of clinical reperfusion, this point stresses the importance reperfusion-associated injury (63).”
InfluentialExercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis
Zhang, H., Zhang, Y., Zhang, J., & Jia, D. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.124.036555 · Cited by 69
“Subsequently, the accumulation of succinate in ischemic myocardium induces vigorous oxidative bursts, exacerbating ischemia–reperfusion injury (IRI), 24 whereas the restoration of succinyl-CoA and oxidative phosphorylation capacity prevented HF progression in MI mice.”
Guo, Y., Zhang, L., Li, F., Hu, C., & Zhang, Z. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.02.052 · Cited by 62
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“Therefore, the increased cytoplasmic NADH redox potential and the activation of MAS should be the driving force for succinate accumulation due to the reversal of SDH activity [24, 26].”
BackgroundMonitoring clinical progression with mitochondrial disease biomarkers
Steele, H. E., Horváth, R., Lyon, J. J., & Chinnery, P. F. (2017) · Brain · doi:10.1093/brain/awx168 · Cited by 63
“Although current focus of this technique is in the assessment of acquired mitochondrial dysfunction arising due to ischaemic and reperfusion insults (Chouchani et al., 2014), the potential application to primary respiratory chain disorders is evident.”
BackgroundKo, S. H., Choi, G. E., Oh, J. Y., Lee, H. J., Kim, J. S., Chae, C. W., Choi, D., & Han, H. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-12692-x · Cited by 64
Involvement of the metabolic sensor GPR81 in cardiovascular control
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“Thus, succinate, which is increased in the situation of ischemia (50),”
BackgroundNemkov, T. G., Sun, K., Reisz, J. A., Yoshida, T., Dunham, A. J., Wen, E. Y., Wen, A. Q., Roach, R. C., Hansen, K. C., Xia, Y., et al. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00175 · Cited by 62
“, ischemic (54) and hemorrhagic hypoxia (55)].”
Hu, H., Nan, J., Sun, Y., Zhu, D., Xiao, C., Wang, Y., Zhu, L., Wu, Y., Zhao, J., Wu, R., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704723114 · Cited by 65
“Interestingly, inhibition of complex I activity could offer significant protection against I/R injury (2, 11), which can be attributed to decreased ROS generation during the reperfusion period (11).”
Background
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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