Comparative Study

. 2014 Nov 20;515(7527):431-435.

doi: 10.1038/nature13909. Epub 2014 Nov 5.

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Edward T Chouchani^#^{1

2}, Victoria R Pell^#², Edoardo Gaude³, Dunja Aksentijević⁴, Stephanie Y Sundier⁵, Ellen L Robb¹, Angela Logan¹, Sergiy M Nadtochiy⁶, Emily N J Ord⁷, Anthony C Smith¹, Filmon Eyassu¹, Rachel Shirley⁷, Chou-Hui Hu², Anna J Dare¹, Andrew M James¹, Sebastian Rogatti¹, Richard C Hartley⁸, Simon Eaton⁹, Ana S H Costa³, Paul S Brookes⁶, Sean M Davidson¹⁰, Michael R Duchen⁵, Kourosh Saeb-Parsy¹¹, Michael J Shattock⁴, Alan J Robinson¹, Lorraine M Work⁷, Christian Frezza³, Thomas Krieg², Michael P Murphy¹

Affiliations

¹ MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
² Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
³ MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
⁴ King's College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
⁵ Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK.
⁶ Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
⁷ Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
⁸ School of Chemistry, University of Glasgow, Glasgow, G12 8TA, UK.
⁹ Unit of Paediatric Surgery, UCL Institute of Child Health, London, WC1N 1EH, UK.
¹⁰ Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
¹¹ University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

^# Contributed equally.

PMID: 25383517
PMCID: PMC4255242
DOI: 10.1038/nature13909

Comparative Study

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Edward T Chouchani et al. Nature. 2014.

. 2014 Nov 20;515(7527):431-435.

doi: 10.1038/nature13909. Epub 2014 Nov 5.

Authors

Affiliations

¹ MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
² Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
³ MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
⁴ King's College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
⁵ Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK.
⁶ Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
⁷ Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
⁸ School of Chemistry, University of Glasgow, Glasgow, G12 8TA, UK.
⁹ Unit of Paediatric Surgery, UCL Institute of Child Health, London, WC1N 1EH, UK.
¹⁰ Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
¹¹ University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

^# Contributed equally.

PMID: 25383517
PMCID: PMC4255242
DOI: 10.1038/nature13909

Abstract

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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Figures

**Extended Data Figure 1**
Comparative analysis of metabolites significantly accumulated in ischaemic conditions. a, Various murine tissues exposed to sufficient periods of ischaemia to prime for reperfusion ROS production were subjected to targeted LC-MS metabolomics analysis and comparison of metabolites that accumulated significantly when compared to normoxic levels. Following this, metabolites were scored according to the prevalence of their accumulation across five ischaemic tissue conditions. B = brain, H = whole heart ischaemia *ex vivo*, HL = LAD ischaemia *in vivo*, K = kidney, L = liver. b, Determination of linearity of the relationship between LC-MS metabolite peak intensity and concentration for CAC and related metabolites. c, Quality control determination of coefficient of variation for LC-MS quantification of CAC and related metabolites.

**Extended Data Figure 2**
Timecourse of succinate levels in the *in vivo* heart during ischaemia and reperfusion and potential metabolic inputs for succinate. a, Time course of succinate levels during myocardial ischaemia and reperfusion for the *in vivo* heart (5 min and 15 min ischaemia n = 4; 30 min ischaemia n = 9; 5 min reperfused n = 5). b, Summary of the three potential metabolic inputs for succinate-directed ischaemic flux. To understand the metabolic pathways that could contribute to succinate production under ischaemia, an updated version of the iAS253 model of cardiac metabolism was employed to simulate ischaemia using flux balance analysis. The model showed three possible mechanisms for producing succinate: from α-ketoglutarate produced by the CAC, derived from glycolysis, fatty acid oxidation, and glutaminolysis (grey box), from succinic semialdehyde produced from the GABA shunt (blue box), and from fumarate produced from the malate-aspartate shuttle and purine nucleotide cycle (red box) via the reversal of SDH. Data are shown as the mean ± s.e.m of at least four biological replicates.

**Extended Data Figure 3**
Metabolic labelling of CAC and proximal metabolites by ¹³C glucose in the ischaemic and normoxic myocardium. Proportional isotopic labelling profile of CAC and proximal metabolites during normoxic and ischaemic myocardial perfusion. Mouse hearts were perfused with 11 mM ¹³C glucose for 10 min followed by either 30 min no flow ischaemia or 30 min normoxic perfusion followed by snap-freezing and LC-MS metabolomic analysis (n = 4). * p < 0.05, ** p < 0.01, *** p < 0.001. Data are shown as the mean ± s.e.m of at least four biological replicates.

**Extended Data Figure 4**
Metabolic labelling of CAC and proximal metabolites by ¹³C palmitate in the ischaemic and normoxic myocardium a, Mouse hearts were perfused with 0.3 mM ¹³C palmitate (+16 labelled) for 10 min resulting in a significant proportion of the endogenous palmitate pool being +16 labelled. Following this, hearts were subjected to either 30 min ischaemia or continued normoxic respiration with ¹³C palmitate followed by snap-freezing and metabolomic analysis. b, Isotopic flux from palmitate to CAC and proximal metabolites following normoxic and ischaemic myocardial respiration. The isotopic profile for each metabolite is expressed as a proportion of the total pool (n = 4). * p < 0.05, ** p < 0.01, *** p < 0.001. Data are shown as the mean ± s.e.m of at least four biological replicates.

**Extended Data Figure 5**
Metabolic labelling of CAC and proximal metabolites by ¹³C glutamine in the ischaemic and normoxic myocardium, and measurement of the effect of inhibition of GABA transaminase succinate accumulation in the ischaemic myocardium. a, Mouse hearts were perfused with 4 mM ¹³C glutamine (+5 labelled) for 10 min followed by either 30 min no flow ischaemia or 30 min normoxic respiration followed by snap freezing and metabolomic analysis. The isotopic profile for each metabolite is expressed as a proportion of the total pool (n=4) b, Additionally, flux to α-KG was determined relative to the proportion of the +5 glutamine pool in the heart (n = 4). c, Perfused mouse hearts were subjected to 30 min no flow ischaemia ± continuous infusion of vigabatrin (Vig; 100, 300, and 700 μM) 10 min prior to ischaemia. Heart tissue was snap frozen and c, GABA and d, succinate abundance quantified relative to normoxic levels by LC-MS (n = 4; ischaemia n = 5). * p < 0.05. Data are shown as the mean ± s.e.m of at least four biological replicates.

**Extended Data Figure 6**
Unabridged metabolic model identifying pathways that can become activated by tissue ischaemia to drive succinate accumulation. To identify the metabolic pathways that could contribute to succinate production under ischaemia, we simulated these conditions using flux balance analysis in conjunction with an expanded version of the iAS253 mitochondrial model of central cardiac metabolism. The major pathways contributing to succinate accumulation (bold red lines) were via fumarate feeding into the reverse activity of SDH. This was produced by the purine nucleotide cycle (PNC) and the malate-aspartate shuttle (MAS), which consumed glucose and aspartate, and also led to significant production of lactate and alanine. Lesser sources of succinate (thin red lines) included glycolysis and glutaminolysis but this was relatively minor as this route was constrained by the overproduction of NADH. In addition a small amount of fumarate was generated by pyruvate carboxylase activity. The GABA shunt did not contribute (black dashed line).

**Extended Data Figure 7**
Effects of dimethyl malonate and dimethyl succinate treatment of cells and *in vivo* on intracellular accumulation of malonate and succinate, and respiration and comparison of ¹³C ischaemic metabolite fluxes to succinate relative to isotopic donor pools. a, Intravenous infusion of dimethyl malonate *in vivo* results in accumulation of malonate in the ischaemic myocardium (n = 4). b,c, C2C12 cells were incubated with: no additions, glucose, 5 mM dimethyl succinate, 5 mM dimethyl malonate, or 5 mM dimethyl malonate and 5 mM dimethyl succinate. Cellular oxygen consumption rate due to (b) ATP synthesis and (c) maximal rates in the presence of FCCP were determined using a Seahorse XF96 analyser (n = 4). d, Mouse hearts were perfused with ¹³C-glucose (+6 labelled), ¹³C-glutamine (+5 labelled), ¹³C-aspartate (+1 labelled), or ¹³C-palmitate (+16 labelled) for 10 min followed by 30 min no flow ischaemia or 30 min normoxic respiration, followed by snap-freezing and metabolomic analysis. To compare the relative magnitude of metabolite flux from each carbon source, ¹³C incorporation to succinate during normoxia and ischaemia was determined relative to the proportion of the labelled pool of the relevant infused ¹³C donor. ¹³C incorporation into succinate was considered in terms of the proportion of the +4 isotope in the entire succinate pool for ¹³C-glucose, ¹³C-glutamine and ¹³C-palmitate infusions; and the proportion of the +1 isotope in the entire pool for the ¹³C-aspartate infusion. (n = 4), *, p < 0.05; ***, p < 0.001. Data are shown as the mean ± s.e.m of at least four biological replicates.

**Extended Data Figure 8**
Predicted changes in pathways of succinate and OXPHOS metabolism during ischaemia and following reperfusion. To determine possible changes in succinate metabolism during ischaemia, reperfusion and normoxia, cardiac metabolism was simulated in these conditions using an expanded version of the iAS253 model with flux balance analysis. The simulations predicted that: a, under ischaemia, complex II ran in reverse by using ubiquinol produced by complex I to reduce fumarate to succinate, thereby acting as a terminal electron acceptor instead of oxygen. Fumarate was produced from the purine nucleotide cycle (PNC) and reversal of the citric acid cycle (CAC). Flux through the rest of the respiratory chain was diminished and AMP was produced from ADP due to insufficient ATP production. b, With oxygen restored complex II metabolised excess succinate. A delay in regenerating AMP to ADP, as typified in the first minute of reperfusion, limited the flux through ATP-synthase. This in turn prevented complex III consuming all the ubiquinol generated by complex II, as the membrane became hyper-polarised. The excess flux of ubiquinol and protons forced complex I to run in reverse, which would generate ROS by RET. c, Once the flux of succinate was reduced to normal levels, as in the transition from late reperfusion to normoxia, the fluxes through the respiratory chain and citric acid cycle returned to normal.

**Extended Data Figure 9**
Tracking DHE oxidation, NAD(P)H reduction state, and mitochondrial membrane potential in primary cardiomyocytes during *in situ* IR. a, Inhibition of mitochondrial complex I RET reduces DHE oxidation on reperfusion (n = 6; rotenone n =4). **b,c** Effect of manipulation of ischaemic succinate levels on NAD(P)H oxidation during early reperfusion (n = 3). Primary rat cardiomyocytes were subjected to 40 min ischaemia followed by reoxygenation and NAD(P)H reduction state was tracked throughout the experiment by measurement of NAD(P)H autofluorescence. Ischaemic buffer contained either no additions, 4 mM dimethyl malonate, or 4 mM dimethyl succinate. Average **(b)** and representative **(c)** traces from each condition are shown. The highlighted window in **(c)** indicates the period of the experiment expanded in detail in (b). d, Effect of inhibition of ischaemic succinate accumulation on mitochondrial membrane potential following late ischaemia (left panels) and early reperfusion (right panels). **e,f,** Primary rat cardiomyocytes were subjected to 40 min ischaemia and reoxygenation and mitochondrial membrane potential was tracked throughout the experiment by measurement of tetramethylrhoadmine (TMRM) fluorescence. Ischaemic buffer contained either no additions or 4 mM dimethyl malonate. **(e),** TMRM signal throughout the entire experiment. **(f)** TMRM signal during the transition from ischaemia to reoxygenation (n = 3). Data are shown as the mean ± s.e.m of at least three biological replicates. Replicates represent separate experiments on independent cell preparations.

**Extended Data Figure 10**
Quantification of CAC intermediates in the heart following infusion of dimethyl succinate and in the brain following infusion of dimethyl malonate, and extended summary cytoprotection and neurological scores of rats subjected to tMCAO IR in vivo ± dimethyl malonate infusion. a, Effect of intravenous infusion of dimethyl succinate on CAC metabolite abundance in the ischaemic and non-ischaemic myocardium(normoxia and peripheral heart tissue + dimethyl succinate n = 3; ischaemia + dimethyl succinate n = 4; α-KG and aconitate in peripheral heart tissue n = 2). b, Profile of mitochondrial CAC metabolite levels following tMCAO ischaemia ± dimethyl malonate (n = 4). c, Representative images of cross-sections from rat brains after undergoing tMCAO *in vivo* ± treatment with dimethyl malonate. Brains were treated with hematoxylin and eosin to delineate infarcted tissue. d, Locomotor and sensorimotor assessment of rats by quantification of average number of footfalls following tCMAO ± dimethyl malonate (control n = 6; dimethyl malonate n = 4). *, p < 0.05; **, p < 0.01. Data are shown as the mean ± s.e.m of at least three biological replicates, unless otherwise stated.

**Figure 1**
Comparative metabolomics identifies succinate as a potential mitochondrial metabolite that drives reperfusion ROS production. a, Comparative metabolomics strategy. b, HIVE plot comparative analysis. All identified metabolites are identified on the horizontal axis, while those accumulated (top axis) or depleted (bottom axis) in a particular ischaemic tissue are indicated by a connecting arc. Metabolites accumulated commonly across all tissues are highlighted. c, Prevalence of accumulation of metabolites in murine tissues during ischaemia. d, Profile of mitochondrial CAC metabolite levels following ischaemia across five ischaemic tissue conditions. (*in vivo* heart n = 5; succinate and fumarate n = 9), (*ex vivo* heart n = 4), (liver n = 4), (brain n = 3), (kidney n = 4). e, Time course of CAC metabolite levels during myocardial ischaemia and reperfusion for 5 min in the *ex vivo* heart (n = 4). f, CAC metabolite levels during *in vivo* myocardial IR in at risk and peripheral heart tissue following ischaemia and after 5 min reperfusion. (n = 5; succinate and fumarate n = 9). g, CAC metabolite levels during *in vivo* brain IR following ischaemia and following 5 min reperfusion (n = 3). h, CAC metabolite levels during *in vivo* kidney IR following ischaemia and after 5 min reperfusion (n = 4; aconitate n = 3). ** p < 0.01, *** p < 0.001. Data are shown as the mean ± s.e.m of at least three biological replicates.

**Figure 2**
Reverse SDH activity drives ischaemic succinate accumulation by the reduction of fumarate. a, Potential inputs to succinate-directed flux by conventional cardiac metabolism and ¹³C-metabolite labelling strategy. **b, c,** ¹³C isotopologue profile of succinate in the normoxic and ischaemic myocardium following infusion of **(b)** ¹³C-glucose and **(c)** ¹³C-palmitate (n = 4). d, Effect of inhibition of GABA shunt with vigabatrin on GABA and succinate levels in the ischaemic myocardium (n = 4; ischaemia n = 5). e, Summary of *in silico* metabolic modelling of potential drivers of ischaemic succinate accumulation, and ¹³C-aspartate metabolic labelling strategy. f, Effect of SDH inhibition by dimethyl malonate on CAC metabolite abundance in the ischaemic myocardium *in vivo* (n = 3). g, Relative incorporation of ¹³C-aspartate to the indicated CAC metabolites in the normoxic and ischaemic myocardium (n = 4). h, Effect on CAC metabolite abundance in the ischaemic myocardium *in vivo* of blocking aspartate entry into the CAC through AOA-mediated inhibition of aspartate aminotransferase, or blocking PNC by inhibition of adenylosuccinate lyase with AICAR (n = 3). * p < 0.05, ** p < 0.01, *** p < 0.001. Data are shown as the mean ± s.e.m of at least three biological replicates.

**Figure 3**
Ischaemic succinate levels control ROS production in adult primary cardiomyocytes and in the heart *in vivo*. **a, b,** DHE oxidation during late ischaemia and early reperfusion ± **(a)** inhibition of ischaemic succinate accumulation (no additions n = 6; dimethyl malonate n = 5) or **(b)** addition of dimethyl succinate during ischaemia (n = 6). c, Inhibition of mitochondrial complex I RET reduces DHE oxidation on reperfusion following addition of dimethyl succinate. Ischaemia (Isch). (n = 5; dimethyl succinate n = 6). d, Effect of dimethyl malonate on mitochondrial repolarisation at reperfusion as determined by the rate of TMRM quenching (n = 3). e, Effect of dimethyl succinate and oligomycin on mitochondrial ROS in aerobic C2C12 myoblasts (n = 4). **f, g.** Effect of inhibition of ischaemic succinate accumulation by dimethyl malonate on mitochondrial ROS during IR injury *in vivo* assessed by **(f)** MitoB oxidation (n = 5; dimethyl malonate n = 6), and by **(g)** aconitase inactivation (n = 4). * p < 0.05, ** p < 0.01. Data are shown as the mean ± s.e.m of at least three biological replicates. For cell data replicates represent separate experiments on independent cell preparations.

**Figure 4**
NADH and AMP sensing pathways drive ischaemic succinate accumulation to control reperfusion pathologies *in vivo* through mitochondrial ROS production. a, Model of succinate accumulation during ischaemia and superoxide formation by RET during reperfusion. b, Representative cross-sections from mouse hearts following myocardial infarction ± inhibition of ischaemic succinate accumulation and reintroduction of ischaemic succinate. Infarcted tissue is white, the rest of the area at risk is red, and non-risk tissue is dark blue. c, Quantification of myocardial infarct size as described in (b). (n = 6). d, Effect of i.v infusion of dimethyl succinate in combination with SDH inhibition by dimethyl malonate on CAC metabolite abundance in the ischaemic myocardium *in vivo* (n = 4). e, Effect of i.v infusion of dimethyl malonate on succinate accumulation in the ischaemic brain *in vivo* (n = 4). **f-h,** Protection by dimethyl malonate against brain IR injury *in vivo*. Quantification of brain infarct volume **(f)** and rostro-caudal infarct distribution **(g)** ± dimethyl malonate following brain IR injury by tMCAO *in vivo* (untreated n = 6; dimethyl malonate n = 4). **(h)** Neurological scores for rats following tMCAO ± dimethyl malonate (untreated n = 6; dimethyl malonate n = 4). * p < 0.05, ** p < 0.01, *** p < 0.001. Data are shown as the mean ± s.e.m of at least three biological replicates, except for h, for which data are median ± C.I.

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Comment in

Biochemistry: succinate strikes.
O'Neill LA. O'Neill LA. Nature. 2014 Nov 20;515(7527):350-1. doi: 10.1038/nature13941. Epub 2014 Nov 5. Nature. 2014. PMID: 25383526 No abstract available.
Mitochondrial metabolomics unravel the primordial trigger of ischemia/reperfusion injury.
Heger M, Reiniers MJ, van Golen RF. Heger M, et al. Gastroenterology. 2015 May;148(5):1071-3. doi: 10.1053/j.gastro.2015.03.041. Epub 2015 Mar 28. Gastroenterology. 2015. PMID: 25824356 No abstract available.
Succinate: A Promising Therapeutic Target for Reperfusion Injury.
Ozpinar A, Weiner GM, Ducruet AF. Ozpinar A, et al. Neurosurgery. 2015 Dec;77(6):N13-4. doi: 10.1227/01.neu.0000473807.30361.29. Neurosurgery. 2015. PMID: 26584319 No abstract available.
Uncovering the origin of oxidative damage in ischaemia-reperfusion injury in the heart.
Figueroa-Juárez E. Figueroa-Juárez E. Nat Rev Endocrinol. 2023 Oct;19(10):560. doi: 10.1038/s41574-023-00881-w. Nat Rev Endocrinol. 2023. PMID: 37495726 No abstract available.

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Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

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