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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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Arias‐Mayenco, I., González‐Rodríguez, P., Torres‐Torrelo, H., Gao, L., Fernández-Agüera, M. C., Bonilla, V., Ortega‐Sáenz, P., & López‐Barneo, J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.009 · Cited by 99
Mitochondrial reactive oxygen species in physiology and disease
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Machine perfusion of the liver and bioengineering
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Collection and Preparation of Clinical Samples for Metabolomics
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Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy
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“In particular, cI generates ROS through reverse electron transfer (RET), which exploits the electrons flowing back from coenzyme Q (CoQ) when this is over-reduced by electrons from cII (Chouchani et al., 2014) or in the presence of drugs or genetic defects that inhibit cIII and/or cIV (Guarás et al.”
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“Several mechanisms including SDH dysfunction, fumarate overproduction and/or TCA acceleration contribute to increased succinate [2, 3].”
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“Of note, succinate can drive mitoROS production at complex I via reverse electron transport (RET) as part of the pathogenesis of ischemia–reperfusion injury (53, 258, 292) (Fig.”
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“Furthermore, LPS induces succinate accumulation, and succinate dehydrogenase rapidly oxidizes this succinate to generate fumarate in a process that requires coenzyme Q (CoQ), which is consumed after LPS stimulation to drive massive ROS production via reverse electron transfer through mitochondrial complex I [117].”
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“The mechanistic details of IRI remain to be elucidated, but dysfunction of the electron transport chain in mitochondria and subsequent anaerobic metabolism are believed to sensitize the cell to excessive ROS formation upon oxygen restoration in the reperfusion stage (33).”
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Background“Oxygen Sensing” by Na,K-ATPase: These Miraculous Thiols
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“It is also reported in the presence of high concentrations of succinate, condition associated with progression of ischemia-reperfusion injury (Drose and Brandt, 2012; Chouchani et al., 2014).”
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How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen‐Consuming Reactions
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“The physiological relevance of complex I backflow is established only in ischemia/reperfusion [13], and these would be expected to occur in normal cell culture only as hypoxiahyperoxia transitions during media changes or passaging.”
BackgroundViability Assessment in Liver Transplantation—What Is the Impact of Dynamic Organ Preservation?
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“The TCA is blocked through the functional relation with complex II, the lower temperature during ischemia, and the lack of energy to fuel the enzymatic activity [40,41].”
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Metabolomics in Diabetic Kidney Disease: Unraveling the Biochemistry of a Silent Killer
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Nanozyme‐Based Regulation of Cellular Metabolism and Their Applications
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“First, as demonstrated in animal models, tissue succinate levels return to baseline within the first few minutes of reperfusion.(2) In PPCI patients, the timing between the onset of reperfusion and subsequent blood sampling is not well defined, given biological heterogeneity in the pathophysiology of ischemia– reperfu…”
BackgroundMethodInfluentialSelf-citationIschemic brain injury: New insights on the protective role of melatonin
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Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo
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Structural basis of species-selective antagonist binding to the succinate receptor
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Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases
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Mitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis
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“Therefore, targeting apoptosis of myofibroblasts with IR-780 improves established lung fibrosis by inducing severe inhibition of succinate dehydrogenase and resulting in excessive ROS in myofibroblasts.”
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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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