Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity
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Succinate accumulates during ischemia, and its oxidation at reperfusion drives injury. The mechanism of ischemic succinate accumulation is controversial and is proposed to involve reversal of mitochondrial complex II. Herein, using stable-isotope-resolved metabolomics, we demonstrate that complex II reversal is possible in hypoxic mitochondria but is not the primary succinate source in hypoxic cardiomyocytes or ischemic hearts. Rather, in these intact systems succinate primarily originates from canonical Krebs cycle activity, partly supported by aminotransferase anaplerosis and glycolysis from glycogen. Augmentation of canonical Krebs cycle activity with dimethyl-α-ketoglutarate both increases ischemic succinate accumulation and drives substrate-level phosphorylation by succinyl-CoA synthetase, improving ischemic energetics. Although two-thirds of ischemic succinate accumulation is extracellular, the remaining one-third is metabolized during early reperfusion, wherein acute complex II inhibition is protective. These results highlight a bifunctional role for succinate: its complex-II-independent accumulation being beneficial in ischemia and its complex-II-dependent oxidation being detrimental at reperfusion.
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FH loss in renal cancer cells leads to increased DNA damage and resistance to ionising radiation due to fumarate-dependent inhibition of mitotic entry after IR even with unrepaired damage.
“It has also recently been shown that FH loss in renal cancer cells leads to increased DNA damage and resistance to ionising radiation (IR), due to a fumarate-dependent inhibition of mitotic entry after IR, even in the presence of unrepaired damage179.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [179]
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Yang, L., Yu, D., Mo, R., Zhang, J., Hu, H., Hu, L., Feng, Y. Y., Wang, S., Zhang, W.-Y., Yin, N., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147597 · Cited by 28 · see citing works
Self-citationRetractedSuccinate 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 · see citing works
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
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., et al. (2014) · Nature · doi:10.1038/nature13909 · Cited by 2,907 · cited 26× · see citing works
“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-citationMills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291 · see citing works
Myocardial Substrate Metabolism in the Normal and Failing Heart
Stanley, W. C., Recchia, F. A., & Lopaschuk, G. D. (2005) · Physiological Reviews · doi:10.1152/physrev.00006.2004 · Cited by 2,042 · see citing works
Glucose feeds the TCA cycle via circulating lactate
Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., et al. (2017) · Nature · doi:10.1038/nature24057 · Cited by 1,721 · see citing works
A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury
Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., Krieg, T., & Murphy, M. P. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.009 · Cited by 752 · see citing works
Alanine: Key Role in Gluconeogenesis
Felig, P., Pozefsk, T., Marlis, E., & Cahill, G. F. (1970) · Science · doi:10.1126/science.167.3920.1003 · Cited by 596 · see citing works
Bernardi, P., & Lisa, F. D. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.09.023 · Cited by 499 · see citing works
LAMBERT, A. J., & BRAND, M. D. (2004) · Biochemical Journal · doi:10.1042/bj20040485 · Cited by 470 · see citing works
Muoio, D. M., Noland, R. C., Kovalik, J.-P., Seiler, S. E., Davies, M. N., DeBalsi, K. L., Ilkayeva, O. R., Stevens, R. D., Kheterpal, I., Zhang, J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.005 · Cited by 372 · see citing works
Self-citationMullen, A. R., Hu, Z., Shi, X., Jiang, L., Boroughs, L. K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L. B., Linehan, W. M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.037 · Cited by 337 · see citing works
MAMMALIAN CARBOHYDRATE METABOLISM
Cori, C. F. (1931) · Physiological Reviews · doi:10.1152/physrev.1931.11.2.143 · Cited by 302 · see citing works
Metformin Activates AMP Kinase through Inhibition of AMP Deaminase
Ouyang, J., Parakhia, R. A., & Ochs, R. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.121806 · Cited by 246 · see citing works
Morciano, G., Giorgi, C., Bonora, M., Punzetti, S., Pavasini, R., Wieckowski, M. R., Campo, G. C., & Pinton, P. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.08.015 · Cited by 229 · see citing works
Diode-like behaviour of a mitochondrial electron-transport enzyme
Sucheta, A., Ackrell, B. A. C., Cochran, B. C., & Armstrong, F. A. (1992) · Nature · doi:10.1038/356361a0 · Cited by 183 · see citing works
Multiple end products of anaerobiosis in diving vertebrates
Hochachka, P. W., Owen, T. G., Allen, J. F., & WHITTOW, G. C. (1975) · Comparative Biochemistry and Physiology Part B Comparative Biochemistry · doi:10.1016/0305-0491(75)90292-8 · Cited by 180 · see citing works
Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells
Smith, B., Schafer, X., Ambeskovic, A., Spencer, C. M., Land, H., & Munger, J. C. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.045 · Cited by 168 · see citing works
Self-citationThe role of succinate and ROS in reperfusion injury – A critical appraisal
Andrienko, T., Pasdois, P., Pereira, G. C., Ovens, M. J., & Halestrap, A. P. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.06.016 · Cited by 158 · see citing works
Insight into SUCNR1 (GPR91) structure and function
Gilissen, J., Jouret, F., Pirotte, B., & Hanson, J. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.01.008 · Cited by 157 · see citing works
Valls-Lacalle, L., Barba, I., Miró‐Casas, E., Alburquerque-Béjar, J. J., Ruiz‐Meana, M., Fuertes‐Agudo, M., Rodríguez‐Sinovas, A., & David Garcia-dorado, A. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv279 · Cited by 149 · see citing works
Maklashina, E., Berthold, D. A., & Cecchini, G. (1998) · Journal of Bacteriology · doi:10.1128/jb.180.22.5989-5996.1998 · Cited by 144 · see citing works
Nonezymatic formation of succinate in mitochondria under oxidative stress
Fedotcheva, N. I., Sokolov, A. P., & Kondrashova, M. N. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.02.012 · Cited by 137 · see citing works
Sanadi, D. R., & Fluharty, A. L. (1963) · Biochemistry · doi:10.1021/bi00903a023 · Cited by 137 · see citing works
Pyruvate Dehydrogenase Influences Postischemic Heart Function
Lewandowski, E. D., & White, L. T. (1995) · Circulation · doi:10.1161/01.cir.91.7.2071 · Cited by 136 · see citing works
The reaction of amino-oxyacetate with pyridoxal phosphate-dependent enzymes
John, R. A., & Charteris, A. (1978) · Biochemical Journal · doi:10.1042/bj1710771 · Cited by 135 · see citing works
Succinate accumulation in man during exercise
Hochachka, P. W., & Dressendorfer, R. H. (1976) · European Journal of Applied Physiology · doi:10.1007/bf00423282 · Cited by 125 · see citing works
Hirst, J., Sucheta, A., Ackrell, B. A. C., & Armstrong, F. A. (1996) · Journal of the American Chemical Society · doi:10.1021/ja9534361 · Cited by 114 · see citing works
Wojtovich, A. P., & Brookes, P. S. (2009) · Basic Research in Cardiology · doi:10.1007/s00395-009-0001-y · Cited by 107 · see citing works
Self-citationMoving Forwards by Blocking Back-Flow
Pell, V. R., Chouchani, E. T., Murphy, M. P., Brookes, P. S., & Krieg, T. (2016) · Circulation Research · doi:10.1161/circresaha.115.306569 · Cited by 101 · see citing works
Self-citationKohlhauer, M., Dawkins, S., Costa, A. S. H., Lee, R., Young, T., Pell, V. R., Choudhury, R. P., Banning, A. P., Kharbanda, R. K., Study, O. A. M. I. (., et al. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.117.007546 · Cited by 91 · see citing works
Tricarboxylic acid cycle metabolites during ischemia in isolated perfused rat heart
PEUHKURINEN, K. J., Takala, T., Nuutinen, E. M., & Hassinen, I. E. (1983) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1983.244.2.h281 · Cited by 89 · see citing works
Valls-Lacalle, L., Barba, I., Miró-Casas, E., Ruiz-Meana, M., Rodríguez-Sinovas, A., & García-Dorado, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-20866-4 · Cited by 88 · see citing works
Purine metabolism after in vivo ischemia and reperfusion in rat skeletal muscle
Idstrom, J. P., Soussi, B., Elander, A., & Bylund‐Fellenius, A. (1990) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1990.258.6.h1668 · Cited by 78 · see citing works
Hohl, C., Oestreich, R., Rösen, P., Wiesner, R., & Grieshaber, M. (1987) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(87)90519-4 · Cited by 68 · see citing works
Metabolism of Pyruvate by the Early Human Embryo1
Butcher, L., Coates, A., Martin, K. L., Rutherford, A. J., & Leese, H. J. (1998) · Biology of Reproduction · doi:10.1095/biolreprod58.4.1054 · Cited by 67 · see citing works
Metabolic fingerprint of ischaemic cardioprotection: importance of the malate-aspartate shuttle
Nielsen, T. T., Støttrup, N. B., Løfgren, B., & Bøtker, H. E. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr051 · Cited by 64 · see citing works
The Mitochondrial Permeability Transition Pore and ATP Synthase
Beutner, G., Alavian, K. N., Jonas, E. A., & Porter, G. A. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_5 · Cited by 61 · see citing works
Anaerobic Rat Heart: Effect of Glucose and Krebs Cycle Metabolites on Rate of Beating
Cascarano, J., Chick, W. L., & Seidman, I. (1968) · Experimental Biology and Medicine · doi:10.3181/00379727-127-32612 · Cited by 60 · see citing works
Støttrup, N. B., Løfgren, B., Birkler, R. I. D., Nielsen, J. M., Wang, L., Caldarone, C. A., Kristiansen, S. B., Contractor, H., Johannsen, M., Bøtker, H. E., et al. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq205 · Cited by 57 · see citing works
The energy-yielding oxidation of NADH by fumarate in submitochondrial particles of rat tissues
Wilson, M. A., & Cascarano, J. (1970) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(70)90158-1 · Cited by 52 · see citing works
Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study
Laplante, A., Vincent, G., Poirier, M., & Rosiers, C. D. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.1.e74 · Cited by 51 · see citing works
Metabolomic and Mass Isotopomer Analysis of Liver Gluconeogenesis and Citric Acid Cycle
Yang, L., Kombu, R. S., Kasumov, T., Zhu, S., Cendrowski, A. V., David, F., Anderson, V. E., Kelleher, J. K., & Brunengraber, H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803454200 · Cited by 48 · see citing works
Nadtochiy, S. M., Urciuoli, W. R., Zhang, J., Schafer, X., Munger, J. C., & Brookes, P. S. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.09.008 · Cited by 48 · see citing works
Self-citationSwain, J. L., Hines, J. J., Sabina, R. L., Harbury, O. L., & Holmes, E. W. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111553 · Cited by 45 · see citing works
The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy
Zhang, J., Nadtochiy, S. M., Urciuoli, W. R., & Brookes, P. S. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00926.2014 · Cited by 36 · see citing works
Self-citationHoberman, H. D., & Prosky, L. (1967) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(67)90135-3 · Cited by 35 · see citing works
Glutamine cycling in isolated working rat heart
Cohen, D. M., Guthrie, P. H., Gao, X., Sakai, R., & Taegtmeyer, H. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00539.2002 · Cited by 23 · see citing works
Pharmacological characterization of the mechanisms underlying the vascular effects of succinate
Leite, L. N., Gonzaga, N. A., Simplicio, J. A., do Vale, G. T., Carballido, J. M., Alves-Filho, J. C., & Tirapelli, C. R. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.07.045 · Cited by 21 · see citing works
Ischemic Heart Arrest: Nitrogenous Metabolism in Energy-Depleted Human Myocardium
Pisarenko, O. I., Studneva, I. M., Portnoy, V. F., Arapov, A. D., & Korostylev, A. M. (2008) · European Surgical Research · doi:10.1159/000128718 · Cited by 2 · see citing works
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1 of the 51 references couldn’t be matched to a known paper.
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Mitochondrial ROS in myocardial ischemia reperfusion and remodeling
Bugger, H., & Pfeil, K. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165768 · Cited by 469 · see citing works
Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death
Bauer, T. M., & Murphy, E. (2020) · Circulation Research · doi:10.1161/circresaha.119.316306 · Cited by 441 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Mitochondrial complex I ROS production and redox signaling in hypoxia
Okoye, C. N., Koren, S. A., & Wojtovich, A. P. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102926 · Cited by 328 · see citing works
Cardiac metabolism as a driver and therapeutic target of myocardial infarction
Zuurbier, C. J., Bertrand, L., Beauloye, C., Andreadou, I., Ruiz‐Meana, M., Jespersen, N. R., Kula‐Alwar, D., Prag, H. A., Bøtker, H. E., Dambrova, M., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15180 · Cited by 239 · see citing works
Self-citation2-Oxoglutarate-dependent dioxygenases in cancer
Losman, J.-A., Koivunen, P., & Kaelin, W. G. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00303-3 · Cited by 225 · see citing works
Fumarate is a terminal electron acceptor in the mammalian electron transport chain
Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., et al. (2021) · Science · doi:10.1126/science.abi7495 · Cited by 221 · see citing works
Oncometabolites in renal cancer
Yong, C., Stewart, G. D., & Frezza, C. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0210-z · Cited by 212 · see citing works
Succinate metabolism and its regulation of host-microbe interactions
Wei, Y., Ma, X., Zhao, J., Wang, X., & Gao, C. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2190300 · Cited by 187 · see citing works
Short-chain fatty acid, acylation and cardiovascular diseases
Chen, X., Chen, X., & Tang, X. (2020) · Clinical Science · doi:10.1042/cs20200128 · Cited by 186 · see citing works
Succinate 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 · see citing works
Dambrova, M., Zuurbier, C. J., Borutaitė, V., Liepinsh, E., & Makrecka‐Kuka, M. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.036 · Cited by 165 · see citing works
Lim, V. G., Bell, R. M., Arjun, S., Kolatsi‐Joannou, M., Long, D. A., & Yellon, D. M. (2019) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2018.10.002 · Cited by 162 · see citing works
Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration
Bae, J., Salamon, R. J., Brandt, E. B., Paltzer, W. G., Zhang, Z., Britt, E. C., Hacker, T. A., Fan, J., & Mahmoud, A. I. (2021) · Circulation · doi:10.1161/circulationaha.120.049952 · Cited by 159 · see citing works
Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling
Wang, T., Xu, Y., Yuan, Y., Xu, P., Zhang, C., Li, F., Wang, L., Yin, C., Zhang, L., Cai, X., et al. (2019) · EMBO Reports · doi:10.15252/embr.201947892 · Cited by 139 · see citing works
Heusch, G., Andreadou, I., Bell, R., Bertero, E., Bøtker, H. E., Davidson, S. M., Downey, J. M., Eaton, P., Ferdinandy, P., Gersh, B. J., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102894 · Cited by 140 · see citing works
Cardioprotection by the mitochondrial unfolded protein response requires ATF5
Wang, Y. T., Lim, Y., McCall, M. N., Huang, K., Haynes, C. M., Nehrke, K. W., & Brookes, P. S. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00244.2019 · Cited by 132 · see citing works
Self-citationMechanism of succinate efflux upon reperfusion of the ischaemic heart
Prag, H. A., Gruszczyk, A. V., Huang, M. M., Beach, T. E., Young, T. J., Tronci, L., Nikitopoulou, E., Mulvey, J. F., Ascione, R., Hadjihambi, A., et al. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa148 · Cited by 112 · see citing works
Onukwufor, J. O., Berry, B. J., & Wojtovich, A. P. (2019) · Antioxidants · doi:10.3390/antiox8080285 · Cited by 112 · see citing works
Ischemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion Injury
Prag, H. A., Aksentijević, D., Dannhorn, A., Giles, A. V., Mulvey, J. F., Sauchanka, O., Du, L., Bates, G. R., Reinhold, J., Kula‐Alwar, D., et al. (2022) · Circulation Research · doi:10.1161/circresaha.121.320717 · Cited by 103 · see citing works
Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O2-Rich Pigment Epithelium
Bisbach, C. M., Hass, D. T., Robbings, B. M., Rountree, A. M., Sadı́lek, M., Sweet, I. R., & Hurley, J. B. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107606 · Cited by 103 · see citing works
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel
Murphy, M. P., & Chouchani, E. T. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01004-8 · Cited by 99 · see citing works
Cancer-derived extracellular succinate: a driver of cancer metastasis
Kuo, C.-C., Wu, J.-Y., & Wu, K. K. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00878-z · Cited by 104 · see citing works
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Saeb‐Parsy, K., Martin, J. L., Summers, D. M., Watson, C. J. E., Krieg, T., & Murphy, M. P. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.08.001 · Cited by 88 · see citing works
Oh, C. J., Kim, M., Lee, J.-M., Kim, D. H., Kim, I., Park, S., Kim, Y., Lee, K., Lee, S., Lim, C. W., et al. (2023) · Kidney International · doi:10.1016/j.kint.2023.06.022 · Cited by 84 · see citing works
Beach, T. E., Prag, H. A., Pala, L., Logan, A., Huang, M. M., Gruszczyk, A. V., Martin, J. L., Mahbubani, K. T. A., Hamed, M. O., Hosgood, S. A., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101640 · Cited by 73 · see citing works
A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation
Kumar, R., Landry, A. P., Guha, A., Vitvitsky, V., Lee, H., Seike, K., Reddy, P. R., Lyssiotis, C. A., & Banerjee, R. V. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101435 · Cited by 70 · see citing works
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Ciccarelli, G., Conte, S., Cimmino, G., Maiorano, P., Morrione, A., & Giordano, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021086 · Cited by 74 · see citing works
Lei, I., Tian, S., Gao, W., Liu, L., Guo, Y., Tang, P., Chen, E., & Wang, Z. (2021) · eLife · doi:10.7554/elife.60311 · Cited by 72 · see citing works
Metabolomics of Endurance Capacity in World Tour Professional Cyclists
San-Millán, I., Stefanoni, D., Martinez, J. L., Hansen, K. C., D’Alessandro, A., & Nemkov, T. G. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00578 · Cited by 69 · see citing works
Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm
Wang, Y., Ge, M., Wang, J., Xu, Y., Wang, N., & Xu, S. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08114-w · Cited by 75 · see citing works
Self-citationSuccinyl-CoA-based energy metabolism dysfunction in chronic heart failure
Takada, S., Maekawa, S., Furihata, T., Kakutani, N., Setoyama, D., Ueda, K., Nambu, H., Hagiwara, H., Handa, H., Fumoto, Y., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203628119 · Cited by 67 · see citing works
Fukushima, 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 65 · see citing works
Self-citationAli, H., Michel, C. R., Lin, Y. H., McKinsey, T. A., Jeong, M. Y., Ambardekar, A. V., Cleveland, J. C., Reisdorph, R. M., Reisdorph, N. A., Woulfe, K. C., et al. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.11.159 · Cited by 60 · see citing works
Jiang, M., Xie, X., Cao, F., & Wang, Y. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.789267 · Cited by 60 · see citing works
Self-citationMDH2 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 58 · see citing works
Succinate in ischemia: where does it come from?
Chinopoulos, C. (2019) · International Journal of Biochemistry and Cell Biology · doi:10.1016/j.biocel.2019.105580 · Cited by 55 · see citing works
Prag, 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 · see citing works
Wang, 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 57 · see citing works
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 · see citing works
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 55 · see citing works
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 52 · see citing works
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 · see citing works
Cox, G., & Gillis, T. E. (2020) · Journal of Experimental Biology · doi:10.1242/jeb.207613 · Cited by 51 · see citing works
Wang, Q., Zuurbier, C. J., Huhn, R., Torregroza, C., Hollmann, M. W., Preckel, B., van den Brom, C. E., & Weber, N. C. (2023) · Cells · doi:10.3390/cells12101432 · Cited by 50 · see citing works
Exploring Perinatal Asphyxia by Metabolomics
Locci, E., Bazzano, G., Demontis, R., Chighine, A., Fanos, V., & d’Aloja, E. (2020) · Metabolites · doi:10.3390/metabo10040141 · Cited by 49 · see citing works
Inefficient Batteries in Heart Failure
Schwartz, B., Gjini, P., Gopal, D. M., & Fetterman, J. L. (2022) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2022.03.017 · Cited by 46 · see citing works
Extracellular Succinate: A Physiological Messenger and a Pathological Trigger
Wu, K. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311165 · Cited by 46 · see citing works
Choi, J., Shoaib, M., Yin, T., Nayyar, G., Shinozaki, K., Stevens, J. F., Becker, L. B., & Kim, J. H. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.012809 · Cited by 45 · see citing works
Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1
Atallah, R., Olschewski, A., & Heinemann, Á. (2022) · Biomedicines · doi:10.3390/biomedicines10123089 · Cited by 43 · see citing works
Bundgaard, A., Ruhr, I. M., Fago, A., & Galli, G. L. J. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.01.002 · Cited by 43 · see citing works
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer
Seyfried, T. N., Lee, D. C., Duraj, T., Ta, N. L., Mukherjee, P., Kiebish, M. A., Arismendi-Morillo, G., & Chinopoulos, C. (2025) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-025-10059-w · Cited by 45 · see citing works
Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis
Antonucci, S., Mulvey, J. F., Burger, N., Sante, M. D., Hall, A. R., Hinchy, E. C., Caldwell, S. T., Gruszczyk, A. V., Deshwal, S., Hartley, R. C., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.034 · Cited by 42 · see citing works
Milliken, A. S., Kulkarni, C. A., & Brookes, P. S. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101733 · Cited by 40 · see citing works
Self-citationEnergy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy
Haas, J., Frese, K., Sedaghat‐Hamedani, F., Kayvanpour, E., Tappu, R., Nietsch, R., Tugrul, O. F., Wisdom, M., Dietrich, C., Amr, A., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041999 · Cited by 40 · see citing works
Milliken, A. S., Nadtochiy, S. M., & Brookes, P. S. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.122.026135 · Cited by 41 · see citing works
Self-citationNanadikar, M. S., Leon, A. M. V., Guo, J., van Belle, G. J., Jatho, A., Philip, E. S., Brandner, A. F., Böckmann, R. A., Shi, R., Zieseniß, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37744-x · Cited by 38 · see citing works
Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction
Tu, C., Caudal, A., Liu, Y., Gorgodze, N., Zhang, H., Lam, C. K., Dai, Y., Zhang, A., Wnorowski, A. N., Wu, M. A., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01134-x · Cited by 38 · see citing works
FNDC-1-mediated mitophagy and ATFS-1 coordinate to protect against hypoxia-reoxygenation
Lim, Y., Berry, B. J., Viteri, S., McCall, M. N., Park, E. C., Rongo, C., Brookes, P. S., & Nehrke, K. W. (2021) · Autophagy · doi:10.1080/15548627.2021.1872885 · Cited by 37 · see citing works
Self-citationWang, X., Li, M., Wang, F., Mao, G.-H., Wu, J., Han, R., Sheng, R., Qin, Z., & Ni, H. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.03.011 · Cited by 36 · see citing works
DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury
Lazzari, F. D., Prag, H. A., Gruszczyk, A. V., Whitworth, A. J., & Bisaglia, M. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101884 · Cited by 36 · see citing works
Cellular crosstalk in cardioprotection: Where and when do reactive oxygen species play a role?
Martins‐Marques, T., Rodríguez‐Sinovas, A., & Girão, H. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.044 · Cited by 38 · see citing works
Dahl, H.-A., Johansen, A., Nilsson, G., & Lefevre, S. (2021) · Metabolites · doi:10.3390/metabo11070435 · Cited by 36 · see citing works
New insights into survival strategies to oxygen deprivation in anoxia‐tolerant vertebrates
Fago, A. (2022) · Acta Physiologica · doi:10.1111/apha.13841 · Cited by 36 · see citing works
Mao, H., Yang, A., Zhao, Y., Lei, L., & Li, H. (2020) · Stem Cells International · doi:10.1155/2020/2016809 · Cited by 35 · see citing works
Succinylation modification: a potential therapeutic target in stroke
Lian, J., Liu, W., Hu, Q., & Zhang, X. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.382229 · Cited by 34 · see citing works
Regulation of metabolism by mitochondrial enzyme acetylation in cardiac ischemia-reperfusion injury
Herr, D. J., Singh, T. N., Dhammu, T. S., & Menick, D. R. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165728 · Cited by 32 · see citing works
The gut-cardiovascular connection: new era for cardiovascular therapy
Cheng, C. K., & Huang, Y. (2021) · Medical Review · doi:10.1515/mr-2021-0002 · Cited by 31 · see citing works
Acute sources of mitochondrial NAD+ during respiratory chain dysfunction
Chinopoulos, C. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113218 · Cited by 29 · see citing works
Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite
Wu, K. K. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.759199 · Cited by 29 · see citing works
Shoaib, M., Choudhary, R. C., Choi, J., Kim, N., Hayashida, K., Yagi, T., Yin, T., Nishikimi, M., Stevens, J. F., Becker, L. B., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-76401-x · Cited by 28 · see citing works
Wang, F., Peng, Q., Liu, J., Alolga, R. N., & Zhou, W. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172417 · Cited by 27 · see citing works
Fluid Brain Glycolysis: Limits, Speed, Location, Moonlighting, and the Fates of Glycogen and Lactate
Barros, L. F., Martín, A. S., Ruminot, I., Sandoval, P. Y., Baeza‐Lehnert, F., Arce‐Molina, R., Rauseo, D., Contreras‐Baeza, Y., Galaz, A., & Valdivia, S. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03005-2 · Cited by 27 · see citing works
Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression
Zhang, S., Liang, Y., Lü, L., Chen, Y., Wu, P., & Wei, D. (2022) · DNA and Cell Biology · doi:10.1089/dna.2021.0345 · Cited by 26 · see citing works
Locci, E., Chighine, A., Noto, A., Ferino, G., Baldi, A., Varvarousis, D., Xanthos, T. T., De‐Giorgio, F., Stocchero, M., & d’Aloja, E. (2021) · Scientific Reports · doi:10.1038/s41598-021-89570-0 · Cited by 25 · see citing works
Unique Metabolomic Profile of Skeletal Muscle in Chronic Limb Threatening Ischemia
Khattri, R. B., Kim, K., Thome, T., Salyers, Z. R., O’Malley, K. A., Berceli, S. A., Scali, S. T., & RYAN, T. E. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030548 · Cited by 24 · see citing works
Sánchez-Pérez, P., Mata, A., Torp, M., López-Bernardo, E., Heiestad, C. M., Aronsen, J. M., de Molina-Iracheta, A., Jiménez‐Borreguero, L. J., García-Rovés, P. M., Costa, A. S. H., et al. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.05.014 · Cited by 24 · see citing works
Metabolic changes in mice cardiac tissue after low-dose irradiation revealed by 1H NMR spectroscopy
Gramatyka, M., Boguszewicz, Ł., Ciszek, M., Gabryś, D., Kulik, R., & Sokol, M. B. (2019) · Journal of Radiation Research · doi:10.1093/jrr/rrz079 · Cited by 24 · see citing works
Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart
Yoval‐Sánchez, B., Ansari, F., James, J., Niatsetskaya, Z. V., Sosunov, S. A., Filipenko, P., Tikhonova, I. G., Ten, V. S., Wittig, I., Rafikov, R., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102258 · Cited by 23 · see citing works
Gruszczyk, A. V., Casey, A. M., James, A. M., Prag, H. A., Burger, N., Bates, G. R., Hall, A. R., Allen, F. M., Krieg, T., Saeb‐Parsy, K., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102368 · Cited by 26 · see citing works
A Spectrofluorometric Method for Real‐Time Graft Assessment and Patient Monitoring
Huwyler, F., Eden, J., Binz, J., Cunningham, L., Silva, R. X. S. D., Clavien, P., Dutkowski, P., Tibbitt, M. W., & Hefti, M. (2023) · Advanced Science · doi:10.1002/advs.202301537 · Cited by 23 · see citing works
Molecular and Cellular Mechanisms of Myocardial Ischemia and Reperfusion Injury: A Narrative Review
Juričić, S., Klac, J., Stojkovic, S. M., Beleslin, B., Tesic, M. B., Jovanović, I., Banovic, M. D., Petrovic, O. M., Aleksandric, S. B., Vasic, N., et al. (2026) · Cells · doi:10.3390/cells15030265 · Cited by 25 · see citing works
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells
Lee, D. C., Ta, N. L., Mukherjee, P., Duraj, T., Domin, M. A., Greenwood, B. P., Karmacharya, S., Narain, N. R., Kiebish, M. A., Chinopoulos, C., et al. (2024) · ASN NEURO · doi:10.1080/17590914.2024.2422268 · Cited by 21 · see citing works
Lindsay, R. T., Dieckmann, S. M., Krzyzanska, D., Manetta-Jones, D., West, J. A., Castro, C., Griffin, J. L., & Murray, A. J. (2021) · eLife · doi:10.7554/elife.71270 · Cited by 19 · see citing works
Stable Isotopes for Tracing Cardiac Metabolism in Diseases
Karlstaedt, A. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.734364 · Cited by 21 · see citing works
Horváth, G., Sváb, G., Komlódi, T., Ravasz, D., Kacsó, G., Dóczi, J., Chinopoulos, C., Ambrus, A., & Tretter, L. (2022) · Antioxidants · doi:10.3390/antiox11081487 · Cited by 21 · see citing works
ALKBH7 mediates necrosis via rewiring of glyoxal metabolism
Kulkarni, C. A., Nadtochiy, S. M., Kennedy, L., Zhang, J., Chhim, S., Alwaseem, H., Murphy, E., Fu, D., & Brookes, P. S. (2020) · eLife · doi:10.7554/elife.58573 · Cited by 19 · see citing works
Self-citationControlled power: how biology manages succinate-driven energy release
Mookerjee, S. A., Gerencser, A. A., Watson, M. A., & Brand, M. D. (2021) · Biochemical Society Transactions · doi:10.1042/bst20211032 · Cited by 21 · see citing works
Gas regulation of complex II reversal via electron shunting to fumarate in the mammalian ETC
Banerjee, R. V., & Kumar, R. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.03.011 · Cited by 19 · see citing works
Perry, J. B., Davis, G. N., Allen, M. E., Makrecka‐Kuka, M., Dambrova, M., Grange, R. W., Shaikh, S. R., & Brown, D. A. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.08.010 · Cited by 19 · see citing works
The regenerative capacity of neonatal tissues
Montero, A. M., & Huang, A. H. (2022) · Development · doi:10.1242/dev.199819 · Cited by 18 · see citing works
Abdullah, S., Ghio, M., Cotton-Betteridge, A., Vinjamuri, A., Drury, R. H., Packer, J., Aras, O. A. Z., Friedman, J. K., Karim, M. S., Engelhardt, D., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf6600 · Cited by 18 · see citing works
Modulation of mitochondrial site-specific hydrogen peroxide efflux by exogenous stressors
Okoye, C. N., Stevens, D., & Kamunde, C. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.234 · Cited by 18 · see citing works
Kim, M.-J., Oh, C., Hong, C., & Jeon, J.-H. (2024) · Journal of Yeungnam Medical Science · doi:10.12701/jyms.2023.01347 · Cited by 17 · see citing works
Ahmad, S., Ali, S., Rehman, D. A. U., Haq, I. U., Liaqat, I., Aftab, M. N., & Shume, T. (2026) · Journal of Medical Microbiology · doi:10.1099/jmm.0.002117 · Cited by 20 · see citing works
Elevated perfusate [Na+] increases contractile dysfunction during ischemia and reperfusion
King, D. R., Padget, R. L., Perry, J. B., Hoeker, G. S., Smyth, J. W., Brown, D. A., & Poelzing, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-74069-x · Cited by 17 · see citing works
Consegal, M., Núñez, N., Barba, I., Benito, B., Ruiz‐Meana, M., Inserte, J., González, I. F., & Rodríguez‐Sinovas, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084151 · Cited by 17 · see citing works
Ravasz, D., Bui, D., Nazarian, S., Pallag, G., Karnok, N., Roberts, J., Marzullo, B. P., Tennant, D. A., Greenwood, B. P., Kitayev, A., et al. (2022) · Scientific Reports · doi:10.1038/s41598-024-51365-4 · Cited by 16 · see citing works
Targeted plasma metabolomics in resuscitated comatose out-of-hospital cardiac arrest patients
Beske, R. P., Henriksen, H., Obling, L. E. R., Kjærgaard, J., Bro‐Jeppesen, J., Nielsen, N., Johansson, P. I., & Hassager, C. (2022) · Resuscitation · doi:10.1016/j.resuscitation.2022.06.010 · Cited by 16 · see citing works
Metabolomics of aging in primary fibroblasts from small and large breed dogs
Brookes, P. S., & Jiménez, A. G. (2021) · GeroScience · doi:10.1007/s11357-021-00388-0 · Cited by 15 · see citing works
Self-citation
- Authors
- Zhang, J., Wang, Y. T., Miller, J. H., Day, M. M., Munger, J. C., & Brookes, P. S.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Brookes, Paul S.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 23
- Issue
- 9
- Pages
- 2617-2628
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6002783
- OpenAlex
- W2805060476
- Cited by
- 203
- References
- 51
- Citations by year
- 2026: 29 · 2025: 20 · 2024: 21 · 2023: 31 · 2022: 30 · 2021: 27 · 2020: 27 · 2019: 16 · 2018: 2
- FWCI
- 13.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- American Historical Association (F30-HL134203, 17PRE33410360)
- National Institutes of Health (R01-HL071158)
- 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 › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- succinate accumulation, myocardial ischemia, TCA cycle, cardiomyocytes, anaplerosis, succinyl-CoA synthetase, substrate-level phosphorylation, ischemia-reperfusion injury, succinate oxidation, myocardial energetics
- MeSH terms
- Transaminases, Animals, Aspartic Acid, Autophagy, Citric Acid Cycle, Energy Metabolism, Glycolysis, Male, Mice, Inbred C57BL, Oxidation-Reduction, Reperfusion Injury, Myocardial Ischemia, Reactive Oxygen Species, Succinic Acid, Electron Transport Complex II, Glycogenolysis
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