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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These ischemic conditions promote reverse electron transfer upon reperfusion, resulting in significant superoxide production from complex I.
“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]
Reverse electron transport ROS generation occurs when succinate is present in high concentration and is responsible in vivo for ROS generated after ischemia upon reperfusion.
“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]
α-KG and succinate regulate the activity of JMJD histone demethylases and TET family 5mC hydroxylases.
“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]
Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, particularly those that regulate succinate levels, which can influence HIF signaling or other pathways.
“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]
Inhibition of SDH by endogenously produced itaconate may buffer against potential oxidative damage that can occur under ischemia/reperfusion conditions.
“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 process was first observed in a model of ischemia-reperfusion (IR) injury, whereby succinate accumulates during ischemia due to a reversal in SDH directionality (57).”
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“In isolated mitochondria supplemented with succinate, RET can produce NADH from NAD via RET through Complex I, however this process is also associated with a significant production of ROS, which is believed to come from the IQ site [109,110].”
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“The abbreviations used are: IBD, inflammatory bowel disease; CRC, colorectal cancer; EPO, erythropoietin; VEGF, vascular endothelial growth factor; ODD, oxygen-dependent degradation domain; PHD, prolyl hydroxylase domain enzyme; VHL, Von Hippel–Lindau; ARNT, aryl hydrocarbon receptor nuclear translocator; HIF, hypoxia…”
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“They have shown that ischemia 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 feeds through to complex I, generating the oxidative stress observed in the first…”
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“After reperfusion, accumulated succinate (a high F/N substrate) is rapidly oxidized by succinate dehydrogenase, indeed driving extensive ROS generation by electrons flowing back to complex I (111).”
Background
- 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 · 2013: 1 · 2012: 1
- 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 › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- 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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