The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Self-citationSuccinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176
Self-citationWhat is flux balance analysis?
Orth, J. D., Thiele, I., & Palsson, B. Ø. (2010) · Nature Biotechnology · doi:10.1038/nbt.1614 · Cited by 3,903
Yellon, D. M., & Hausenloy, D. J. (2007) · New England Journal of Medicine · doi:10.1056/nejmra071667 · Cited by 3,797
Ischemia and reperfusion—from mechanism to translation
Eltzschig, H. K., & Eckle, T. D. L. G. (2011) · Nature Medicine · doi:10.1038/nm.2507 · Cited by 3,468
Srere, P. A. (1969) · Methods in Enzymology · doi:10.1016/0076-6879(69)13005-0 · Cited by 2,005
Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0
Schellenberger, J., Que, R., Fleming, R. M. T., Thiele, I., Orth, J. D., Feist, A. M., Zielinski, D. C., Bordbar, A., Lewis, N. E., Rahmanian, S., et al. (2011) · Nature Protocols · doi:10.1038/nprot.2011.308 · Cited by 1,835
Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury
Murphy, E., & Steenbergen, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00024.2007 · Cited by 1,504
Pacher, P., Nivorozhkin, A., & Szabó, C. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.1.6 · Cited by 1,218
Direct measurement of free radical generation following reperfusion of ischemic myocardium.
Zweier, J. L., Flaherty, J. T., & Weisfeldt, M. L. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.5.1404 · Cited by 1,189
Cited by
Sorted by citations
Items 601–700 of 1,003
White-Springer, S. H., McDermott, M. M., Sufit, R. L., Kosmac, K., Bugg, A. W., González‐Freire, M., Ferrucci, L., Tian, L., Zhao, L., Gao, Y., et al. (2016) · Journal of Translational Medicine · doi:10.1186/s12967-016-1030-6 · Cited by 62
Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness
Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00396 · Cited by 60
“During inflammation, succinate may be secreted by inflammatory macrophages and accumulate into TME (74), as reported in murine ischemic tissues (75), central nervous system inflammation and in rheumatoid arthritis inflammation.”
BackgroundLee, H., & José, P. A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.670076 · Cited by 68
“ROS are also produced by the flavin in ETC Complex I, under the condition of reverse electron transport (Chouchani et al., 2014), when the protonmotive force (pmf, including Δψm and ΔpH) is increased (Scialò et al.”
BackgroundWang, J., Chen, P., Cao, Q., Wang, W., & Chang, X. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/9205908 · Cited by 62
“Disorders of internal calcium homeostasis lead to increased levels of apoptosis and decreased levels of mitophagy [20].”
Metabolic sensing and control in mitochondria
Liu, Y., & Birsoy, K. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.016 · Cited by 65
Towards an Understanding of Energy Impairment in Huntington’s Disease Brain
Dubinsky, J. M. (2017) · Journal of Huntington s Disease · doi:10.3233/jhd-170264 · Cited by 63
“Given that SDH inhibition is protective in ischemiareperfusion injury [129], some of the same shifts in metabolic flux demonstrated by this acute insult may contribute to striatal energetic defects in HD, although this hypothesis remains to be explicitly tested.”
BackgroundInfluentialTFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance
Lynch, M. R., Tran, M. T., Ralto, K. M., Zsengellér, Z. K., Raman, V., Bhasin, S. S., Sun, N., Chen, X., Brown, D., Rovira, I. I., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126749 · Cited by 61
“motes cell death by producing excessive free radicals and other proapoptotic mediators (4, 5).”
Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function
Zhao, H., Raines, L. N., & Huang, S. C. (2020) · Cells · doi:10.3390/cells9030562 · Cited by 62
“However, high levels of succinate oxidation favor the process of reverse electron transport (RET) at complex I, which is associated with significant release of mtROS leading to oxidative damage and cell death [12,15].”
BackgroundLiu, M., Zhou, X., Li, Y., Ma, S., Pan, L., Zhang, X., Zheng, W., Wu, Z., Wang, K., Ahsan, A., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102323 · Cited by 59
“Stressed mitochondria and peroxisomes are the primary source of reactive oxygen species (ROS) in ischemic neurons [13,14].”
BackgroundReverse electron transfer is activated during aging and contributes to aging and age‐related disease
Rimal, S., Tantray, I., Li, Y., Khaket, T. P., Li, Y., Bhurtel, S., Li, W., Zeng, C., & Lu, B. (2023) · EMBO Reports · doi:10.15252/embr.202255548 · Cited by 60
“However, excessive RET-ROS is implicated in ischemia – reperfusion injury (Chouchani et al , 2014; Brand et al , 2016).”
InfluentialFukushima, C. T., Dancil, I.-S., Clary, H., Shah, N., Nadtochiy, S. M., & Brookes, P. S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103047 · Cited by 68
“However, upon tissue reperfusion the rapid oxidation of succinate by mitochondrial Cx-II is a key driver of reactive oxygen species (ROS) generation [1,6], which along with Ca 2 + overload triggers opening of the mitochondrial permeability transition (PT) pore and subsequent cell death [7 – 10].”
BackgroundInfluentialSelf-citationMechanisms of postischemic cardiac death and protection following myocardial injury
Mastoor, Y., Murphy, E., & Román, B. (2025) · Journal of Clinical Investigation · doi:10.1172/jci184134 · Cited by 68
“Reverse electron transport (RET) driven by an increase in succinate generated during ischemia is another important source of ROS during reperfusion, and blocking RET is cardioprotective (159).”
Thiol switches in mitochondria: operation and physiological relevance
Riemer, J., Schwarzländer, M., Conrad, M., & Herrmann, J. M. (2015) · Biological Chemistry · doi:10.1515/hsz-2014-0293 · Cited by 58
“Upon reoxygenation (reperfusion) rapid reactivation of complex I is a major source of the deleterious ROS production in cardiomyocytes (Yellon and Hausenloy, 2007; Prime et al., 2009; Chouchani et al., 2014).”
BackgroundHollander, M. R., de Waard, G. A., Konijnenberg, L. S. F., Putten, R. M. E. M.-V., van den Brom, C. E., Paauw, N. J., de Vries, H. E., van de Ven, P. M., Aman, J., Amerongen, G. P. V. N., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157233 · Cited by 60
Slade, L., Chalker, J., Kuksal, N., Young, A., Gardiner, D., & Mailloux, R. J. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.05.010 · Cited by 60
Zou, R., Shi, W., Tao, J., Li, H., Lin, X., Yang, S., & Hua, P. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.11.005 · Cited by 61
Chalker, J., Gardiner, D., Kuksal, N., & Mailloux, R. J. (2017) · Redox Biology · doi:10.1016/j.redox.2017.12.006 · Cited by 60
Gong, P., Zhang, Z., Zou, C., Tian, Q., Chen, X., Hong, M., Liu, X., Chen, Q., Zhou, X., Li, M., et al. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.08.003 · Cited by 60
Jiang, L., Zeng, H., Ni, L., Qi, L., Xu, Y., Xia, L., Yu, Y., Liu, B., Yang, H. Q., Hao, H., et al. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7624 · Cited by 61
“During the ischemic stage, disrupted metabolism activates succinate dehydrogenase and thereby increasing succinate accumulation, which drives mitochondrial reactive oxygen species (ROS) generation (9).”
Mitochondrial functions and rare diseases
Dard, L., Blanchard, W., Hubert, C., Lacombe, D., & Rossignol, R. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.100842 · Cited by 65
Jiang, M., Xie, X., Cao, F., & Wang, Y. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.789267 · Cited by 61
“SDH inhibition with malonate before ischemia or at the onset of reperfusion reduces infarct size in isolated mice hearts through inhibiting ROS generation and mPTP opening (84, 92).”
BackgroundMethodInfluentialMDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle
Molinié, T., Cougouilles, E., David, C., Cahoreau, E., Portais, J., & Mourier, A. (2022) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2022.148532 · Cited by 60
Xie, S., Xing, Y., Shi, W., Zhang, M., Chen, M., Fang, W., Liu, S., Zhang, T., Zeng, X., Chen, S., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.07.022 · Cited by 61
Modeling Heart Diseases on a Chip: Advantages and Future Opportunities
Mourad, O., Yee, R., Li, M., & Nunes, S. S. (2023) · Circulation Research · doi:10.1161/circresaha.122.321670 · Cited by 62
Степанова, А., Shurubor, Y. I., Valsecchi, F., Manfredi, G., & Galkin, A. S. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.06.002 · Cited by 58
Human Tissue-Engineered Model of Myocardial Ischemia–Reperfusion Injury
Chen, T. F., & Vunjak‐Novakovic, G. (2018) · Tissue Engineering Part A · doi:10.1089/ten.tea.2018.0212 · Cited by 62
“Antioxidants have shown mixed results in preclinical studies and small clinical trials, and more recently, the specific targeting of mitochondrial ROS generation has become of interest.(74) Early results have indicated that these therapies can reduce IRI 720 CHEN AND VUNJAK-NOVAKOVIC”
BackgroundRedox signaling in heart failure and therapeutic implications
Weissman, D., & Maack, C. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.05.013 · Cited by 60
Ichihara, G., Katsumata, Y., Sugiura, Y., Matsuoka, Y., Maeda, R., Endo, J., Anzai, A., Shirakawa, K., Moriyama, H., Kitakata, H., et al. (2023) · Circulation Research · doi:10.1161/circresaha.123.323517 · Cited by 63
“Accumulation of succinate during ischemia and its conversion to fumarate during reperfusion 3,56 was confirmed by tissue metabolomics and extracellular fluid analysis in this study (Figures S1 and S2).”
BackgroundNanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications
Meng, T., He, D., Han, Z., Shi, R., Wang, Y., Ren, B., Zhang, C., Mao, Z., Luo, G., & Deng, J. (2024) · Nano-Micro Letters · doi:10.1007/s40820-024-01455-9 · Cited by 63
“This process upregulates the proinflammatory gene profile to drive the M1 response [11, 200].”
BackgroundSIRT3 in Cardiac Physiology and Disease
Koentges, C., Bode, C., & Bugger, H. (2016) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2016.00038 · Cited by 58
“Since succinate accumulates during ischemia and drives mitochondrial ROS generation at the onset of reperfusion by increasing reverse electron transport in the respiratory chain, the authors proposed that inhibition of succinate dehydrogenase may restore IR injury to WT levels by reducing succinate-driven ROS producti…”
BackgroundLi, J., Yang, Y., Li, L., Zhang, L., Liu, Q., Liu, K., Li, P., Liu, B., & Qi, L. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.017 · Cited by 55
“The conventional direction of succinate dehydrogenase (SDH) in the CAC is to catalyze succinate for fumarate formation, but in ischemic heart, the altered mitochondrial function increases succinate accumulation due to the reversal of SDH, a process proposed to be related to the malate/aspartate shuttle (MAS) [14].”
BackgroundInfluentialReperfusion therapy—What’s with the obstructed, leaky and broken capillaries?
Granger, D. N., & Kvietys, P. R. (2017) · Pathophysiology · doi:10.1016/j.pathophys.2017.09.003 · Cited by 59
Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β -cells
Plecitá‐Hlavatá, L., Engstová, H., Ježek, J., Holendová, B., Tauber, J. A., Petrásková, L., Křen, V., & Ježek, P. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/1826303 · Cited by 57
“, succinate accumulation, in cardiomyocytes during ischemia, while the concomitant superoxide burst is the primary damaging agent upon reperfusion in ischemic heart disease [45, 48].”
Succinate in ischemia: Where does it come from?
Chinopoulos, C. (2019) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2019.105580 · Cited by 55
Mitochondria orchestrate macrophage effector functions in atherosclerosis
Dumont, A., Lee, M., Barouillet, T., Murphy, A. J., & Yvan‐Charvet, L. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100922 · Cited by 60
Exploiting metabolic vulnerabilities for personalized therapy in acute myeloid leukemia
Stuani, L., Sabatier, M., & Sarry, J. (2019) · BMC Biology · doi:10.1186/s12915-019-0670-4 · Cited by 66
Mitochondrial K+ channels and their implications for disease mechanisms
Checchetto, V., Leanza, L., Stefani, D. D., Rizzuto, R., Gulbins, E., & Szabó, I. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107874 · Cited by 58
Narrative review of metabolomics in cardiovascular disease
Müller, J., Bertsch, T., Volke, J., Schmid, A., Klingbeil, R., Metodiev, Y., Karaca, B., Kim, S.-H., Lindner, S., Schupp, T., et al. (2021) · Journal of Thoracic Disease · doi:10.21037/jtd-21-22 · Cited by 58
“A mouse model simulating ischemia-reperfusion injury could show that succinate accumulates in ischemic heart tissue and succinate oxidation is a key actor for mitochondrial ROS accumulation and injury (161).”
BackgroundD’Alessandro, A., Akpan, I. J., Thomas, T., Reisz, J. A., Cendali, F. I., Gamboni, F., Nemkov, T. G., Thangaraju, K., Katneni, U., Tanaka, K. A., et al. (2021) · Cells · doi:10.3390/cells10092293 · Cited by 57
“, urate and xanthine), hallmarks of ischemic [39] and hemorrhagic [36] hypoxic organ damage, increased with age.”
Wei, X.-H., Chen, J., Wu, X.-F., Zhang, Q., Xia, G., Chu, X., Xia, H., Lin, S. H., & Shang, H.-C. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156260 · Cited by 57
NADH reductive stress drives metabolic reprogramming
Yang, R., Guo, Z., & Li, B. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.07.005 · Cited by 61
Ma, T., Chen, T., Li, P., Ye, Z., Zhai, W., Jia, L., Chen, W., Sun, A., Huang, Y. X. R., Wei, S., et al. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2016.02.013 · Cited by 58
Redox Signaling from Mitochondria: Signal Propagation and Its Targets
Ježek, P., Holendová, B., & Plecitá‐Hlavatá, L. (2020) · Biomolecules · doi:10.3390/biom10010093 · Cited by 59
“Succinate accumulation => RET Hypoxia/reperfusion Indry (heart) [35]”
BackgroundHofmann, J. D., Otarashvili, G., Mészáros, A., Ebner, S., Weißenbacher, A., Cardini, B., Oberhuber, R., Resch, T., Öfner, D., Schneeberger, S., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093132 · Cited by 59
“Pharmacolog cal nhibition of SDH significantly educes mROS production [14], which in turn results in the reduction of the Coenzyme Q (CoQ) pool, leading to proton pumping by mitochondrial complexes III and IV.”
BackgroundInfluentialPrag, H. A., Pala, L., Kula‐Alwar, D., Mulvey, J. F., Du, L., Beach, T. E., Booty, L. M., Hall, A. R., Logan, A., Sauchanka, V., et al. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-07033-6 · Cited by 57
“accumulation of succinate during ischemia, as shown previously [10].”
BackgroundInfluentialSelf-citationMorphometric examination of mitochondrial ultrastructure in aging cardiomyocytes
Eldarov, C. M., Vays, V. B., Vangeli, I. M., Kolosova, N. G., & Bakeeva, L. E. (2015) · Biochemistry (Moscow) · doi:10.1134/s0006297915050132 · Cited by 57
Novel Molecular Targets Participating in Myocardial Ischemia-Reperfusion Injury and Cardioprotection
Liu, N., Wu, M., Chen, C., Fujino, M., Huang, J., Zhu, P., & Li, X. (2019) · Cardiology Research and Practice · doi:10.1155/2019/6935147 · Cited by 55
“Mouse Rotenone, MitoSNO8 Complex I RET protein Inhibit complex I RET to abolish ischemic succinate and dimethyl succinate-driven DHE oxidation [26]”
BackgroundIntertwined Relationship of Mitochondrial Metabolism, Gut Microbiome and Exercise Potential
Imdad, S., Lim, W., Kim, J., & Kang, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052679 · Cited by 60
“The circular double stranded mt-DNA consists of a guanine-rich heavy strand and a cytosine-rich light strand, while most of the mt-DNA components are coded by the former strand [82].”
BackgroundWang, X., Zhang, X., Cao, K. J., Zeng, M., Fu, X., Zheng, A., Zhang, F., Gao, F., Zou, X., Li, H., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31548-1 · Cited by 58
Chavda, V. K., & Lu, B. (2023) · Antioxidants · doi:10.3390/antiox12040895 · Cited by 61
“The manipulation of succinate accumulation or oxidation through SDH inhibition has also been shown to protect against I/R injury [70].”
BackgroundImmunometabolism at the Heart of Cardiovascular Disease
DeBerge, M., Chaudhary, R. K., Schroth, S. L., & Thorp, E. B. (2023) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2022.12.010 · Cited by 59
“Within mitochondria, inflammatory macrophage activation leads to increased levels of the tricarboxylic acid cycle (TCA) metabolite succinate, which is oxidized by succinate dehydrogenase (SDH), increasing mitochondrial membrane potential and mitochondrial ROS production.52 This is important because mitochondrial ROS a…”
BackgroundHe, H., Liu, P., & Li, P. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s428024 · Cited by 56
“3,5,6 8 Therefore, there is an urgent need to explore novel therapeutic strategies capable of effectively inhibiting oxidative stress and maintaining a dynamic equilibrium in mitochondria, which is crucial for preventing early pathological changes during I/R and enhancing the heart’s resistance to…”
BackgroundAlburquerque-Béjar, J. J., Barba, I., Inserte, J., Miró‐Casas, E., Ruiz‐Meana, M., Poncelas, M., Vilardosa, Ú., Valls-Lacalle, L., Rodríguez‐Sinovas, A., & David Garcia-dorado, A. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv171 · Cited by 56
“Complex 1 is a major source of reactive oxygen species at reperfusion and its transient inhibition reduces reperfusion injury.(33) In particular, S-nitrosation at mitochondrial complex 1 has been demonstrated to decrease oxidative damage and necrosis in vivo by slowing the reactivation of mitochondrial respiration dur…”
BackgroundRYAN, T. E., Schmidt, C. A., Green, T. D., Spangenburg, E. E., Neufer, P. D., & McClung, J. M. (2016) · Diabetes · doi:10.2337/db16-0387 · Cited by 55
“This is consistent with findings in cardiac mitochondria, in which electroncarrying reducing equivalents and upstream metabolites build up during ischemia, and ROS production increases upon reperfusion when oxygen levels return (24).”
BackgroundResultInfluentialThe metabolic axis of macrophage and immune cell polarization
Hobson-Gutierrez, S., & Carmona‐Fontaine, C. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.034462 · Cited by 57
“…by inflammatory signals [such as LPS (Nishi et al., 2008; Tannahill et al., 2013)] and by pseudohypoxia, when the accumulation of metabolites, such as succinate (Chouchani et al., 2014; Tannahill et al., 2013) or low pH (Intlekofer et al., 2017), stabilize HIF-1 α even under normal oxygen tension.”
Miyazaki, Y., Inaoka, D. K., Shiba, T., Saimoto, H., Sakura, T., Amalia, E., Kido, Y., Sakai, C., Nakamura, M., Moore, A. L., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00997 · Cited by 56
Ishihara, G., Kawamoto, K., Komori, N., & Ishibashi, T. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.135 · Cited by 56
D’Alessandro, A., Slaughter, A. L., Peltz, E. D., Moore, E. E., Silliman, C. C., Wither, M. J., Nemkov, T. G., Bacon, A. W., Fragoso, M., Banerjee, A. M., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0612-z · Cited by 55
Prophylactic Edaravone Prevents Transient Hypoxic-Ischemic Brain Injury
Sun, Y., Li, Y., Wali, B., Li, Y., Lee, J., Heinmiller, A., Abe, K., Stein, D. G., Mao, H. Z., Sayeed, I., et al. (2015) · Stroke · doi:10.1161/strokeaha.115.009162 · Cited by 55
“Edaravone Abates tHI-Induced Oxidative Stress in the Brain Parenchyma and Vascular Wall Tissue ischemia accumulates succinate in the mitochondria, which drives superoxide formation on reperfusion by reverse electron transport.(25) To detect superoxide, tHI-injured mice were intravenously injected with hydroethidine, w…”
MethodIntegration of superoxide formation and cristae morphology for mitochondrial redox signaling
Plecitá‐Hlavatá, L., & Ježek, P. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.09.010 · Cited by 57
Zhang, W., Chen, C., Wang, J., Liu, L., He, Y., & Chen, Q. (2018) · Physiology · doi:10.1152/physiol.00030.2017 · Cited by 56
“sensitive to sudden changes in oxygen levels during I/R (24, 29, 48, 55, 76).”
BackgroundTFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance
Lynch, M. R., Tran, M. T., Ralto, K. M., Zsengellér, Z. K., Raman, V., Bhasin, S. S., Sun, N., Chen, X., Brown, D., Rovira, I. I., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.142898 · Cited by 53
Zhu, J., Wang, Y., Chai, X., Qian, K., Zhang, L.-W., Peng, P., Chen, P.-M., Cao, J.-F., Qin, Z., Sheng, R., et al. (2019) · Acta Pharmacologica Sinica · doi:10.1038/s41401-019-0301-1 · Cited by 55
“However, during patency of the coronary artery, the myocardium may be further damaged by a sudden increase in oxygen, a process that is known as I/R injury [2].”
BackgroundCobley, J. N. (2020) · Antioxidants · doi:10.3390/antiox9100933 · Cited by 57
“Reverse electron transfer (RET) catalyzed superoxide production was discovered by Chance and co-workers in 1967 [71], and was considered irrelevant, until Murphy’s group showed that RET contributed to cardiac ischemia reperfusion injury (IRI) in 2013–2014 [72,73].”
BackgroundPCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells
Bluemel, G., Planque, M., Madreiter‐Sokolowski, C. T., Haitzmann, T., Hrzenjak, A., Graier, W. F., Fendt, S., Olschewski, H., & Leithner, K. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.09.007 · Cited by 54
Li, F., Liu, D., Liu, M., Ji, Q., Zhang, B., Mei, Q., Cheng, Y., & Zhou, S. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01445-2 · Cited by 54
Exploiting synergistic effect of CO/NO gases for soft tissue transplantation using a hydrogel patch
Tang, X., Ren, J., Wei, X., Wang, T., Li, H., Sun, Y., Liu, Y., Chi, M., Zhu, S., Lu, L., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37959-y · Cited by 54
Complex II Biology in Aging, Health, and Disease
Goetzman, E. S., Gong, Z., Zhang, B. B., & Muzumdar, R. H. (2023) · Antioxidants · doi:10.3390/antiox12071477 · Cited by 54
Preventing mitochondrial reverse electron transport as a strategy for cardioprotection
Prag, H. A., Murphy, M. P., & Krieg, T. (2023) · Basic Research in Cardiology · doi:10.1007/s00395-023-01002-4 · Cited by 58
“Succinate was significantly accumulated in numerous ischaemic mouse tissues, including the heart [40].”
BackgroundInfluentialSelf-citationMitochondria sense bacterial lactate and drive release of neutrophil extracellular traps
Wise, A. D., TenBarge, E. G., Mendonça, J. D. C., Mennen, E. C., McDaniel, S. R., Reber, C. P., Holder, B. E., Bunch, M. L., Belevska, E., Marshall, M. G., et al. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.02.003 · Cited by 54
Ralph, S. J., Pritchard, R., Rodríguez‐Enríquez, S., Moreno‐Sánchez, R., & Ralph, R. K. (2015) · Pharmaceuticals · doi:10.3390/ph8010062 · Cited by 55
“production that occurs along the respiratory chain depends on the type of oxidizable substrate that is predominately being used and the rate of electron transport [43,44,50,53].”
BackgroundRedox signaling in the cardiomyocyte: From physiology to failure
Santos, C. X. C., Raza, S., & Shah, A. M. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.03.002 · Cited by 54
Andrienko, T., Pasdois, P., Rossbach, A. M., & Halestrap, A. P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167300 · Cited by 55
“47 nmol/mg dw (n = 6) after 30 min ischemia as described by Chouchani et al [20].”
InfluentialA novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance
Bailey, J. D., Shaw, A., Fischer, R., Ryan, B. J., Kessler, B. M., McCullagh, J., Wade‐Martins, R., Channon, K. M., & Crabtree, M. J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.012 · Cited by 53
“[27] proposed that succinate accumulation (resulting from ischaemia) is the major driver of mitochondrial superoxide production via complex I.”
BackgroundWang, H., Huwaimel, B., Verma, K., Miller, J. E., Germain, T., Kinarivala, N., Pappas, D., Brookes, P. S., & Trippier, P. C. (2017) · ChemMedChem · doi:10.1002/cmdc.201700196 · Cited by 52
Self-citationZhao, P., Zhou, W., Zhang, Y., Li, J., Zhao, Y., Pan, L., Shen, Z., Chen, W., & Hui, J. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14972 · Cited by 54
Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases
Moreno, C., Santos, R. M., Burns, R., & Zhang, W. C. (2020) · Cancers · doi:10.3390/cancers12113237 · Cited by 56
“Succinate is known to accumulate during cardiac ischemia, which is then consumed during reperfusion and leads to oxidative damage due to increased ROS production [75].”
BackgroundAdaptations to a hypoxic lifestyle in naked mole-rats
Pamenter, M. E. (2022) · Journal of Experimental Biology · doi:10.1242/jeb.196725 · Cited by 57
Iron deficiency for prognosis in acute coronary syndrome – A systematic review and meta-analysis
Reinhold, J., Papadopoulou, C., Baral, R., & Vassiliou, V. S. (2020) · International Journal of Cardiology · doi:10.1016/j.ijcard.2020.12.021 · Cited by 53
Kelmanson, I. V., Shokhina, A. G., Kotova, D. A., Pochechuev, M. S., Ivanova, A. D., Kostyuk, A. I., Panova, A. S., Borodinova, A. A., Solotenkov, M. A., Stepanov, E. A., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102178 · Cited by 53
“Several sources of ROS generation in stroke have been identified in cells, the NADPH-oxidase (NOXs) family and the mitochondrial respiratory chain being the main of them [11,15 – 18].”
BackgroundIschemic stroke: From pathological mechanisms to neuroprotective strategies
Jiang, Y., Liu, Z., Liao, Y., Sun, S., Dai, Y., & Tang, Y. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.1013083 · Cited by 58
“In the early stage of perfusion, the accumulated FADH2 activates SDH and drives mitochondria to produce a large amount of ROS via reverse electron transfer (RET) (105).”
BackgroundBaik, A. H., Haribowo, A. G., Chen, X., Queliconi, B. B., Barrios, A. M., Garg, A., Maishan, M., Campos, A. R., Matthay, M. A., & Jain, I. H. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.013 · Cited by 56
Hoiland, R. L., Robba, C., Menon, D. K., Citerio, G., Sandroni, C., & Sekhon, M. S. (2023) · Intensive Care Medicine · doi:10.1007/s00134-023-07165-x · Cited by 60
Complex II ambiguities—FADH2 in the electron transfer system
Gnaiger, E. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105470 · Cited by 55
“…ranging from metabolism in anaerobic animals (14, 15), thermodynamic ef fi ciency of anaerobic and aerobic ATP production (16), reverse electron transfer and production of reactive oxygen species (17 – 19), hypoxia and ischemia-reperfusion injury (20), to evolution of metabolic pathways (21, 22).”
BackgroundBundgaard, A., James, A. M., Joyce, W., Murphy, M. P., & Fago, A. (2018) · Journal of Experimental Biology · doi:10.1242/jeb.174391 · Cited by 55
“hypoxia in mammals (Chouchani et al., 2014) and during anoxia in turtles (A.”
BackgroundSelf-citationSynapse Pruning: Mitochondrial ROS with Their Hands on the Shears
Cobley, J. N. (2018) · BioEssays · doi:10.1002/bies.201800031 · Cited by 56
Wyss, R. K., Méndez‐Carmona, N., Arnold, M., Segiser, A., Mueller, M., Dutkowski, P., Carrel, T. P., & Longnus, S. (2020) · American Journal of Transplantation · doi:10.1111/ajt.16258 · Cited by 53
Lassen, T. R., Just, J., Hjortbak, M. V., Jespersen, N. R., Stenz, K. T., Gu, T., Yan, Y., Su, J., Hansen, J., Bæk, R., et al. (2021) · Basic Research in Cardiology · doi:10.1007/s00395-021-00856-w · Cited by 54
Kamarauskaitė, J., Banienė, R., Trumbeckas, D., Strazdauskas, A., & Trumbeckaitė, S. (2020) · BioMed Research International · doi:10.1155/2020/8855585 · Cited by 52
“[7] observed the accumulation of succinate after ischemia and noticed that ischemic succinate accumulation was responsible for mitochondrial ROS production during reperfusion through a reverse electron transport at mitochondrial complex I [7].”
BackgroundInfluentialThe CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia
Kozawa, K., Sekai, M., Ohba, K., Ito, S., Sako, H., Maruyama, T., Kakeno, M., Shirai, T., Kuromiya, K., Kamasaki, T., et al. (2021) · Current Biology · doi:10.1016/j.cub.2021.04.078 · Cited by 50
Aczél, T., Körtési, T., Kun, J., Urban, P. P., Bauer, W., Herczeg, R., Farkas, R., Kovács, K., Vásárhelyi, B., Karvaly, G., et al. (2021) · The Journal of Headache and Pain · doi:10.1186/s10194-021-01285-9 · Cited by 52
Li, W., Liu, D., Xu, J., Zha, J., Wang, C., An, J., Xie, Z., & Qiao, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02942-z · Cited by 52
“Procoagulant factors, such as thrombin, GPVI, and ROS, play critical roles in mediating cerebral I/R injury [7, 24, 25].”
BackgroundRoma, L. P., Deponte, M., Riemer, J., & Morgan, B. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7449 · Cited by 51
“It will, thus, be particularly interesting to apply these sensors to rigorously scrutinize and test long-standing hypotheses in redox biology, including those of hypoxia-induced ROS production and ROS increase after ischemia-reperfusion (10, 11, 23, 25, 26, 83, 96).”
Ngo, D. T. M., Sverdlov, A. L., Karki, S., Macartney-Coxson, D. P., Stubbs, R. S., Farb, M. G., Carmine, B. J., Hess, D. T., Colucci, W. S., & Gokce, N. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00227.2018 · Cited by 51
Immunometabolism of Phagocytes and Relationships to Cardiac Repair
Zhang, S., Bories, G. F. P., Lantz, C. W., Emmons, R., Becker, A., Liu, E., Abecassis, M. M., Yvan‐Charvet, L., & Thorp, E. B. (2019) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2019.00042 · Cited by 54
“Decreasing ischemic succinate accumulation is sufficient to ameliorate ischemia reperfusion injury in murine models of heart attacks (107).”
BackgroundDarius, T., Vergauwen, M., Smith, T. B., Gerin, I., Joris, V., Mueller, M., Aydın, S., Muller, X., Schlegel, A. A., Nath, J., et al. (2020) · American Journal of Transplantation · doi:10.1111/ajt.15800 · Cited by 52
ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine
Fontana, D., Mauri, M., Renso, R., Docci, M., Crespiatico, I., Røst, L. M., Jang, M., Niro, A., D’Aliberti, D., Massimino, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19721-w · Cited by 52
Lee, T.-L., Lee, M., Chen, Y., Lee, Y., Lai, T.-C., Lin, H. Y., Hsu, L., Sung, H., Lee, C., & Chen, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.604700 · Cited by 53
“ROS are produced by mitochondria due to aerobic metabolism during I/R (Chouchani et al., 2014).”
BackgroundCox, G., & Gillis, T. E. (2020) · Journal of Experimental Biology · doi:10.1242/jeb.207613 · Cited by 54
Kim, K., Anderson, E. M., Scali, S. T., & RYAN, T. E. (2020) · Antioxidants · doi:10.3390/antiox9121304 · Cited by 53
“Although the exact cause of mitochondrial ROS during ischemia reperfusion remains complicated, an emerging evidence centers on succinate accumulation during ischemia and reverse electron flow through complex I (NADH dehydrogenase) of the electron transport system during reperfusion [107].”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
