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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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“This overflow of electrons from complex II powers both ATP synthesis (via transfer of these electrons forward to complexes III and IV) and ROS (via reverse flow of electrons back to complex I)[26].”
BackgroundMitochondrial Cx43, an important component of cardiac preconditioning
Rodríguez‐Sinovas, A., Ruiz‐Meana, M., Denuc, A., & David Garcia-dorado, A. (2017) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2017.06.011 · Cited by 46
Lipid metabolic reprogramming in hepatic ischemia–reperfusion injury
Monga, S. P. (2018) · Nature Medicine · doi:10.1038/nm.4468 · Cited by 46
Kang, J., Choi, H., & Lee, S. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14212 · Cited by 46
“Succinate-driven reverse electron transport through mitochondrial complex I is a wellestablished source of ROS after prolonged ischaemia (Chouchani et al., 2014).”
BackgroundJohannsson, O. E., Giacomin, M., Sadauskas‐Henrique, H., Campos, D. F., Mota, S. B., Heinrichs-Caldas, W., Baptista, R. B., Wood, C. M., de Almeida‐Val, V. M. F., & Val, A. L. (2018) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2018.05.019 · Cited by 45
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Oldford, C., Kuksal, N., Gill, R., Young, A., & Mailloux, R. J. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.02.012 · Cited by 46
Pheochromocytomas and Paragangliomas: From Genetic Diversity to Targeted Therapies
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“Studies using in vivo and in vitro models have shown that loss of succinate dehydrogenase activity results in: (i) abnormal activation of hypoxia-signaling pathway in the presence of oxygen (pseudohypoxia) and angiogenesis [26]; (ii) increased production of reactive oxygen species (ROS) [27]; and (iii) impeded repair…”
BackgroundNew opportunities for targeting redox dysregulation in cardiovascular disease
Bubb, K. J., Drummond, G. R., & Figtree, G. A. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz183 · Cited by 50
Wong, H. S., Monternier, P., & Brand, M. D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.09.006 · Cited by 46
Makkos, A., Ágg, B., Petrovich, B., Varga, Z. V., Görbe, A., & Ferdinandy, P. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.04.034 · Cited by 49
Esparza‐Moltó, P. B., Romero-Carramiñana, I., de Arenas, C. N., Pereira, M. P., Blanco, N., Pardo, B., Bates, G. R., Sánchez‐Castillo, C., Artuch, R., Murphy, M. P., et al. (2021) · PLoS Biology · doi:10.1371/journal.pbio.3001252 · Cited by 47
“We investigated mtROS production by reverse electron transfer (RET) [32,33] through complex I in isolated brain mitochondria using succinate to reduce the CoQ pool and generate Δ p [34].”
Self-citationFrom blood to brain: blood cell-based biomimetic drug delivery systems
Li, Y., Wu, J., Liu, J., Qiu, X., Xu, W., Tang, T., & Xiang, D. (2021) · Drug Delivery · doi:10.1080/10717544.2021.1937384 · Cited by 46
“During an ischemic stroke cascade, insufficient endogenous antioxidants fail to detoxify excessive reactive oxygen species (ROS) entities, which would react with complex materials, including lipids, proteins, and nucleic acids, in blood vessels of the brain (Chouchani et al., 2014).”
BackgroundMitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology
Fujiwara, H., Seike, K., Brooks, M. D., Mathew, A. V., Kovalenko, I., Pal, A., Lee, H., Peltier, D., Kim, S. H., Liu, C., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01048-3 · Cited by 45
A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans
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Review on the protective mechanism of astragaloside IV against cardiovascular diseases
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“It has previously been reported that succinic acid accumulates during myocardial ischemia and can be consumed in large quantities during reperfusion to produce ROS (Chouchani et al., 2014).”
BackgroundHou, Z., & Brenner, J. S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103185 · Cited by 47
“ROS initiate a cascade of reactions that damage cellular structures, leading to oxidative stress, and further aggravating calcium overload and inflammation [16,17].”
BackgroundGlutamine metabolism drives succinate accumulation in plasma and the lung during hemorrhagic shock
Slaughter, A. L., D’Alessandro, A., Moore, E. E., Banerjee, A. M., Silliman, C. C., Hansen, K. C., Reisz, J. A., Fragoso, M., Wither, M. J., Bacon, A. W., et al. (2016) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000001256 · Cited by 45
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Quintana, D. D., Garcia, J. A., Sarkar, S. N., Jun, S., Engler-Chiurazzi, E. B., Russell, A. E., Cavendish, J. Z., & Simpkins, J. W. (2018) · Mitochondrion · doi:10.1016/j.mito.2018.12.004 · Cited by 46
Microglia immunometabolism: From metabolic disorders to single cell metabolism
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Ablation of Toll-like receptor 9 attenuates myocardial ischemia/reperfusion injury in mice
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“Isolated mouse hearts were Langendorff-perfused as previously described [8,9].”
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“An example of this phenomenon is that a few studies found succinate accumulation in either the plasma, brain, or heart tissues as a consequence of ischemia,(19,52,53) while another study found that succinate increased universally when the brain, heart, kidney, or liver were individually subjected to ischemia via direc…”
ResultZhang, W., Jin, Y., Wang, D., & Cui, J. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.01.002 · Cited by 43
Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production
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“Furthermore, transient inhibition of the electron transport chain at the onset of reperfusion reduces ROS and decreases cell death and the size of myocardial infarction in animal models [20,21].”
BackgroundResultMolani‐Gol, R., & Kheirouri, S. (2021) · Nutrition and Cancer · doi:10.1080/01635581.2021.1897631 · Cited by 49
Chen, Q., Thompson, J., Hu, Y., & Lesnefsky, E. J. (2021) · Aging · doi:10.18632/aging.202858 · Cited by 45
“ROS generated by reverse electron flow contributes to cardiac injury during reperfusion [95].”
BackgroundSong, M., Zhou, Y., & Fan, X. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02795-6 · Cited by 45
Machine Perfusion for Extended Criteria Donor Livers: What Challenges Remain?
Widmer, J. D., Eden, J., Carvalho, M. F., Dutkowski, P., & Schlegel, A. A. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11175218 · Cited by 45
Yu, D., Cai, W., Shen, T., Wu, Y., Ren, C., Li, T., Hu, C., Zhu, M., & Yu, J. (2023) · Cell Biology and Toxicology · doi:10.1007/s10565-023-09791-z · Cited by 47
“Mitochondria are the main parts of aerobic respiration to provide energy and the main source of intracellular ROS (Chouchani et al. 2014).”
BackgroundSelf-citationXing, X., Gong, Z., Chen, C., Lin, Y., Liu, P., Xiao, T., Yu, H., Li, Y., Lin, Y., Tan, G., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.123059 · Cited by 44
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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