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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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Zhang, J., Wang, Y. T., Miller, J. H., Day, M. M., Munger, J. C., & Brookes, P. S. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.104 · Cited by 203
“Evidence for model A comes in part from in vivo studies, interpretation of which is complicated by the presence of other organs (Chouchani et al., 2014), and from artificial systems such as isolated mitochondria (Sanadi and Fluharty, 1963; Wilson and Cascarano, 1970) (Figure 2B).”
BackgroundMethodResultInfluentialSelf-citationWallert, M., Ziegler, M., Wang, X., Maluenda, A. C., Xu, X., Yap, M. L., Witt, R., Giles, C., Kluge, S., Hortmann, M., et al. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101292 · Cited by 203
“bination of extensive inflammatory and oxidative stress [3].”
BackgroundThe multifaceted regulation of mitophagy by endogenous metabolites
Zhang, T., Liu, Q., Gao, W., Sehgal, S. A., & Wu, H. (2021) · Autophagy · doi:10.1080/15548627.2021.1975914 · Cited by 209
“Early studies revealed that succinate stabilizes the transcription factor HIF1A [216], boosts ROS generation [217], and modifies certain substrate proteins through succinylation [218].”
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Cytokine-like Roles for Metabolites in Immunity
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Intermediates of Metabolism: From Bystanders to Signalling Molecules
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“However, succinate is known to accumulate many fold under such conditions (up to 10 15 mM) [15, 25].”
BackgroundHosgood, S. A., Callaghan, C. J., Wilson, C. H., Smith, L., Mullings, J., Mehew, J., Oniscu, G. C., Phillips, B. L., Bates, L., & Nicholson, M. L. (2023) · Nature Medicine · doi:10.1038/s41591-023-02376-7 · Cited by 192
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“Accumulation of reactive oxygen species (ROS) causes a variety of injuries, including mitochondrial damage and myocardial apoptosis [6].”
BackgroundZhang, L., Wei, T., Li, Y., Li, J., Fan, Y., Huang, F., Cai, Y., Ma, G., Liu, J., Chen, Q., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.031139 · Cited by 193
Kazak, L., Chouchani, E. T., Stavrovskaya, I. G., Lu, G. Z., Jedrychowski, M. P., Egan, D. F., Kumari, M., Kong, X., Erickson, B. K., Szpyt, J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705406114 · Cited by 195
“Under conditions of high membrane potential, succinate reduces ubiquinone (Q) to ubiquinol (QH2), resulting in a reverse electron flow through complex I (11, 30).”
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Antioxidant peptides, the guardian of life from oxidative stress
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Short-chain fatty acid, acylation and cardiovascular diseases
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Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling
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“The heart contains a large number of mitochondria, which is an essential source of cellular ROS production.(36) In addition, endothelial cells and neutrophils in the heart are also important sources of ROS production.”
BackgroundTrumpff, C., Michelson, J., Lagranha, C. J., Taleon, V., Karan, K. R., Sturm, G., Lindqvist, D., Fernström, J., Moser, D., Kaufman, B. A., et al. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.04.002 · Cited by 190
“For example, functional neurons can release and transfer damaged whole mitochondria to neighboring astrocytes for either recycling or clearance (Chung-ha et al., 2014), effectively outsourcing the degradation of dysfunctional mitochondria.”
BackgroundMetabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications
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Regulation of redox balance in cancer and T cells
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“Though very high levels of ROS, especially OH•, produce oxidative damage and cell death, a pool of spatially localized and moderate concentration of ROS are required for many biological processes including cell survival, death, proliferation, and immune responses (1-3).”
BackgroundCharacterization of the cardiac succinylome and its role in ischemia–reperfusion injury
Boylston, J. A., Sun, J., Chen, Y., Guček, M., Sack, M. N., & Murphy, E. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.09.005 · Cited by 181
Modelling mitochondrial ROS production by the respiratory chain
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Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it?
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Oncometabolites: Unconventional triggers of oncogenic signalling cascades
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“During ischemia, succinate signi fi cantly accumulates in multiple organs and its oxidation is responsible for ROS generation during reperfusion [91].”
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Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?
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“During ischemia, rewiring of the Krebs cycle reduces fumarate levels, leading to succinate accumulation (18).”
InfluentialSelf-citationROS signaling and redox biology in endothelial cells
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“The mitochondria are considered the prominent sources of endogenous ROS under physiological conditions and deregulated mitochondrial ROS production is associated to many cardiovascular alterations [99].”
BackgroundClearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery
Dookun, E., Walaszczyk, A., Redgrave, R., Palmowski, P., Tual‐Chalot, S., Suwana, A., Chapman, J., Jirkovsky, E., Donastorg Sosa, L., Gill, E., et al. (2020) · Aging Cell · doi:10.1111/acel.13249 · Cited by 173
“A key component of IRI is the increased generation of reactive oxygen species (Chouchani et al., 2014) which is thought to contribute to tissue dysfunction.”
BackgroundUse the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species
Berry, B. J., Trewin, A. J., Amitrano, A. M., Kim, M., & Wojtovich, A. P. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.03.025 · Cited by 180
“Increased ΔpH drives RET ROS production during IR [6, 174], but in this case, decreased ΔpH resulted in oxidative damage in mitochondria post IR [196].”
BackgroundInfluentialProteomic responses to environmentally induced oxidative stress
Tomanek, L. (2015) · Journal of Experimental Biology · doi:10.1242/jeb.116475 · Cited by 173
“Importantly, recent evidence suggests that a transfer of electrons (as FADH) to CoQ via electron transfer flavoprotein, originating from β-oxidation, does not cause RET and therefore ROS production from complex I, opposite to the action of succinate dehydrogenase (SDH), which transfers electrons (as FADH) from succina…”
BackgroundCoenzyme Q biosynthesis and its role in the respiratory chain structure
Alcázar‐Fabra, M., Navas, P., & Brea‐Calvo, G. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.03.010 · Cited by 180
Mitochondrial function, ornamentation, and immunocompetence
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“…in the mitochondrial lumen, increases in concentration in macrophages stimulated by TLR4 recognition of bacterial LPS and enhances the production of proinflammatory cytokines (Wang, Malo & Hekimi, 2010; Tannahill et al., 2013; Chouchani et al., 2014; Mills & O’Neill, 2014; Weinberg et al., 2015).”
BackgroundSuccinate accumulation drives ischaemia-reperfusion injury during organ transplantation
Martin, J. L., Costa, A. S. H., Gruszczyk, A. V., Beach, T. E., Allen, F. M., Prag, H. A., Hinchy, E. C., Mahbubani, K. T. A., Hamed, M. O., Tronci, L., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0115-y · Cited by 166
Self-citation
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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