Endogenous and exogenous succinate: what is significant functional difference? Or is it not?

Orlov Yu.P.; Petrov A.Yu.; Kovalenko A.L.

doi:https://doi.org/10.17116/anaesthesiology2025061125

Recommended articles:

Therapeutic potential of quercetin and its derivatives against COVID-19. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(5):44-50

Proinflammatory cytokines — as a marker of the effectiveness of neuroprotection in children with perinatal nervous system damage. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(6):62-66

Experimental and clinical evaluation of the safety and efficacy of Polydexa spray with phenylephrine in acute rhinosinusitis. Russian Bulletin of Otorhinolaryngology. 2025;(4):39-46

The role of Inflasinusans in the treatment of acute rhinosinusitis. Russian Bulletin of Otorhinolaryngology. 2025;(4):64-71

Use of ozone therapy in the treatment of complications following penetrating keratoplasty for rosacea-associated keratitis. Russian Annals of Ophthalmology. 2025;(4):66-72

Psychodermatological aspects of psoriasis, current condition of problem. Russian Journal of Clinical Dermatology and Venereology. 2025;(4):403-411

The use of grape polyphenols in combination with magnetic therapy in patients with bronchial asthma who have suffered a new coronavirus infection. Problems of Balneology, Physiotherapy and Exercise Therapy. 2025;(4):14-19

Antioxidant therapy for the correction of nitrosative stress in inflammatory diseases of the nasal cavity. Russian Rhinology. 2025;(3):191-196

Effect of perioperative fluid therapy on ischemia-reperfusion syndrome in elective percutaneous coronary interventions. Russian Journal of Cardiology and Cardiovascular Surgery. 2025;(5):586-592

Results of a multicenter international study on the efficacy and safety of Remaxol in patients with drug-induced liver injury during antitumor therapy. P.A. Herzen Journal of Oncology. 2025;(5):26-33

Abstract:

This review is devoted to physiological and pathophysiological role of endogenous and exogenous succinate in ensuring effective oxidative phosphorylation process in mitochondrial respiratory chain. The last one ensures synthesis of adenosine triphosphate (ATP) under normoxic and hypoxic conditions. Both endogenous and exogenous succinate performs the same functions in providing substrate for mitochondrial respiratory chain and has no different pharmacological effects. Under hypoxia and inflammation, succinate acts as a signaling molecule indicating severity of hypoxia and inflammation, as well as suppression of oxidative phosphorylation. Accumulation of succinate under hypoxia and inflammation has compensatory and protective (antioxidant) nature that is realized under regression of inflammation through reperfusion and reoxygenation. During these periods, succinate is oxidized faster than synthesized. Exogenous succinate plays a substitute role and functions similar to endogenous substrate providing energy potential of mitochondrial respiratory chain.

Keywords:

hypoxia

inflammation

succinate

succinate dehydrogenase

Krebs cycle

oxidative phosphorylation

mitochondrial respiratory chain

Authors:

Orlov Yu.P.

Omsk State Medical University

ORCID: 0000-0003-1291-6019

Petrov A.Yu.

Golikov Scientific Clinical Center of Toxicology

ORCID: 0000-0001-6204-0145

Kovalenko A.L.

Golikov Scientific Clinical Center of Toxicology

ORCID: 0000-0003-3695-2671

Received:

19.06.2025

Accepted:

02.09.2025

Close metadata

References:

Wang Q, Li M, Zeng N, Zhou Y, Yan J. Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease. Experimental Biology and Medicine. 2023;248(3):263-270. https://doi.org/10.1177/15353702221147567
Romantsov MG, Goryacheva LG, Sukhanov DS, Sologub TV, Kovalenko AL, Petrov AYu, Ivanov AK, Anikina OV. Correction of medicinal liver lesions with succinate-containing drugs. Vestnik Sankt-Peterburgskoj gosudarstvennoj meditsinskoj akademii im. I.I. Mechnikova. 2008;4(29):215-220. (In Russ.).
Tretter L, Patocs A, Chinopoulos C. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. Biochimica et Biophysica Acta. 2016;1857(8):1086-1101. https://doi.org/10.1016/j.bbabio.2016.03.012
Chance B, Williams GR. A method for the localization of sites for oxidative phosphorylation. Nature. 1955;176(4475):250-254.
Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. VI. The effects of adenosine diphosphate on azide-treated mitochondria. The Journal of Biological Chemistry. 1956;221(1):477-489.
Chance B, Hollunger G. The interaction of energy and electron transfer reactions in mitochondria. I. General properties and nature of the products of succinate-linked reduction of pyridine nucleotide. The Journal of Biological Chemistry. 1961;236:1534-1543.
Handbook of Flavoproteins. Volume 2: Complex Flavoproteins, Dehydrogenases and Physical Methods. Hille R, Miller S, Palfey B, eds. Berlin: Walter de Gruyter & Co. 2013;2:141-436.
Ousaka D, Nishibori M. A new approach to combat the sepsis including COVID-19 by accelerating detoxification of hemolysis-related DAMPs. Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica. 2022;157(6):422-425. https://doi.org/10.1254/fpj.22073
Hawkins BJ, Levin MD, Doonan PJ, Petrenko NB, Davis CW, Patel VV, Madesh M. Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. The Journal of Biological Chemistry. 2010;285(34):26494-505. https://doi.org/10.1074/jbc.M110.143164
Hirota K. Basic biology of hypoxic responses mediated by the transcription factor HIFs and its implication for medicine. Biomedicines. 2020;8(2):32.
Prag HA, Gruszczyk AV, Huang MM, Beach TE, Young T, Tronci L, Nikitopoulou E, Mulvey JF, Ascione R, Hadjihambi A, Shattock MJ, Pellerin L, Saeb-Parsy K, Frezza C, James AM, Krieg T, Murphy MP, Aksentijević D. Mechanism of succinate efflux upon reperfusion of the ischaemic heart. Cardiovascular Research. 2021;117(4):1188-1201. https://doi.org/10.1093/cvr/cvaa148
Kohlhauer M, Dawkins S, Costa ASH, Lee R, Young T, Pell VR, Choudhury RP, Banning AP, Kharbanda RK; Oxford Acute Myocardial Infarction (OxAMI) Study; Saeb-Parsy K, Murphy MP, Frezza C, Krieg T, Channon KM. Oxford Acute Myocardial Infarction (OxAMI) Study et al. Metabolomic Profiling in Acute ST-Segment-Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia-Reperfusion Injury. Journal of the American Heart Association. 2018;7(8):e007546. https://doi.org/10.1161/JAHA.117.007546
Wu B, Luo H, Zhou X, Cheng CY, Lin L, Liu BL, Liu K, Li P, Yang H. Succinate-induced neuronal mitochondrial fission and hexokinase II malfunction in ischemic stroke: Therapeutical effects of kaempferol. Biochimica et Biophysica Acta. Molecular Basis of Disease. 2017;1863(9):2307-2318. https://doi.org/10.1016/j.bbadis.2017.06.011
Correa PR, Kruglov EA, Thompson M, Leite MF, Dranoff JA, Nathanson MH. Succinate is a paracrine signal for liver damage. Journal of Hepatology. 2007; 47:262-269.
Lu YT, Li LZ, Yang YL, Yin X, Liu Q, Zhang L, Liu K, Liu B, Li J, Qi LW. Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling. Cell Death and Disease. 2018;9:672. https://doi.org/10.1038/s41419-018-0708-5
Mills EL, Harmon C, Jedrychowski MP, Xiao H, Garrity R, Tran NV, Bradshaw GA, Fu A, Szpyt J, Reddy A, Prendeville H, Danial NN, Gygi SP, Lynch L, Chouchani ET. UCP1 governs liver extracellular succinate and inflammatory pathogenesis. Nature Metabolism. 2021;3(5):604-617. https://doi.org/10.1038/s42255-021-00389-5
Connors J, Dawe N, Van Limbergen J. The Role of Succinate in the Regulation of Intestinal Inflammation. Nutrients. 2018;11(1):25. https://doi.org/10.3390/nu11010025
Fremder M, Kim SW, Khamaysi A, Shimshilashvili L, Eini-Rider H, Park IS, Hadad U, Cheon JH, Ohana E. A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state. Cell Reports. 2021;36(6):109521. https://doi.org/10.1016/j.celrep.2021.109521
Monfort-Ferré D, Caro A, Menacho M, Martí M, Espina B, Boronat-Toscano A, Nuñez-Roa C, Seco J, Bautista M, Espín E, Megía A, Vendrell J, Fernández-Veledo S, Serena C. The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn’s Disease. Journal of Crohn’s and Colitis. 2022;16(10):1571-1583. https://doi.org/10.1093/ecco-jcc/jjac069
Xu J, Zheng Y, Zhao Y, Zhang Y, Li H, Zhang A, Wang X, Wang W, Hou Y, Wang J. Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis. Frontiers in Immunology. 2022;13:817572. https://doi.org/10.3389/fimmu.2022.817572
Abdullah S, Ghio M, Cotton-Betteridge A, Vinjamuri A, Drury R, Packer J, Aras O, Friedman J, Karim M, Engelhardt D, Kosowski E, Duong K, Shaheen F, McGrew PR, Harris CT, Reily R, Sammarco M, Chandra PK, Pociask D, Kolls J, Katakam PV, Smith A, Taghavi S, Duchesne J, Jackson-Weaver O. Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage. Science Advances. 2023;9(24):eadf6600. https://doi.org/10.1126/sciadv.adf6600
Litvitsky PF. Inflammation. Voprosy sovremennoj pediatrii. 2006;5(5):64-71. (In Russ.).
Solberg R, Enot D, Deigner HP, Koal T, Scholl-Bürgi S, Saugstad OD, Keller M. Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs. PLoS One. 2010;5(3):e9606. https://doi.org/10.1371/journal.pone.0009606
Lukyanova LD, Kirova YI. Mitochondria-controlled signaling mechanisms of brain protection in hypoxia. Frontiers in Neuroscience. 2015;9:320. https://doi.org/10.3389/fnins.2015.00320
Lazarev VV, Anchutin PE. Effects of succinates on the inflammatory response: a review. Annals of Critical Care. 2023;3:155-165. (In Russ.). https://doi.org/10.21320/1818-474X-2023-3-155-165
Ryan DG, O’Neill LAJ. Krebs Cycle Reborn in Macrophage Immunometabolism. Annual Review of Immunology. 2020;38:289-313. https://doi.org/10.1146/annurev-immunol-081619-104850
Maklashina E, Kotlyar AB, Karliner JS, Cecchini G. Effect of oxygen on activation state of complex I and lack of oxaloacetate inhibition of complex II in Langendorff perfused rat heart. FEBS Letters. 2004;556(1-3):64-68.
Murphy MP, Chouchani ET. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel. Nature Chemical Biology. 2022; 18(5):461-469. https://doi.org/10.1038/s41589-022-01004-8
Murphy MP, O’Neill LAJ. Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers. Cell. 2018;174(4):780-784. https://doi.org/10.1016/j.cell.2018.07.030
Liu H, Zhang H, Zhang X, Chen Q, Xia L. Role of succinic acid in the regulation of sepsis. International Immunopharmacology. 2022;110:109065. https://doi.org/10.1016/j.intimp.2022.109065
Reddy A, Bozi LHM, Yaghi OK, Mills EL, Xiao H, Nicholson HE, Paschini M, Paulo JA, Garrity R, Laznik-Bogoslavski D, Ferreira JCB, Carl CS, Sjøberg KA, Wojtaszewski JFP, Jeppesen JF, Kiens B, Gygi SP, Richter EA, Mathis D, Chouchani ET. pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise. Cell. 2020;183(1):62-75.e17. https://doi.org/10.1016/j.cell.2020.08.039
Zhang J, Wang YT, Miller JH, Day MM, Munger JC, Brookes PS. Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity. Cell Reports. 2018;23(9):2617-2628. https://doi.org/10.1016/j.celrep.2018.04.104
Kushnir MM, Komaromy-Hiller G, Shushan B, Urry FM, Roberts WL. Analysis of dicar boxylic acids by tandem mass spectrometry. High-throughput quantita tive measurement of methylmalonic acid in serum, plasma, and urine. Clinical Chemistry. 2001;47(11):1993-2002.
Ariza AC, Deen PM, Robben JH. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. Frontiers in Endocrinology. 2012;3:22.
Lukyanova LD. The signaling role of mitochondria in adaptation to hypoxia. Fiziologicheskij zhurnal. 2013;59(6):141-154. (In Russ.).
Xu J, Pan H, Xie X, Zhang J, Wang Y, Yang G. Inhibiting Succinate Dehydrogenase by Dimethyl Malonate Alleviates Brain Damage in a Rat Model of Cardiac Arrest. Neuroscience. 2018;393:24 32. https://doi.org/10.1016/j.neuroscience.2018.09.041
Lukyanova LD. Signal’nye mekhanizmy gipoksii. M.: Rossijskaya akademiya nauk; 2019:215. (In Russ.).
Lukyanova LD, Kirova YI. Mitochondria-controlled signaling mechanisms of brain protection in hypoxia. Frontiers in Neuroscience. 2015;9:320. https://doi.org/10.3389/fnins.2015.00320
Lukyanova L, Germanova E, Khmil N, Pavlik L, Mikheeva I, Shigaeva M, Mironova G. Signaling role of mitochondrial enzymes and ultrastructure in the formation of molecular mechanisms of adaptation to hypoxia. International Journal of Molecular Sciences. 2021;22 (16):8636. https://doi.org/10.3390/ijms22168636
Li X, Mao M, Zhang Y, Yu K, Zhu W. Succinate Modulates Intestinal Barrier Function and Inflammation Response in Pigs. Biomolecules. 2019;9:486. https://doi.org/10.3390/biom9090486
Andrienko TN, Pasdois P, Pereira GC, Ovens MJ, Halestrap AP. The role of succinate and ROS in reperfusion injury — A critical appraisal. Journal of Molecular and Cellular Cardiology. 2017;110:1-14. https://doi.org/10.1016/j.yjmcc.2017.06.016
Ashrafian H, Czibik G, Bellahcene M, Aksentijević D, Smith AC, Mitchell SJ, Dodd MS, Kirwan J, Byrne JJ, Ludwig C, Isackson H, Yavari A, Støttrup NB, Contractor H, Cahill TJ, Sahgal N, Ball DR, Birkler RI, Hargreaves I, Tennant DA, Land J, Lygate CA, Johannsen M, Kharbanda RK, Neubauer S, Redwood C, de Cabo R, Ahmet I, Talan M, Günther UL, Robinson AJ, Viant MR, Pollard PJ, Tyler DJ, Watkins H. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metabolism. 2012;15(3):361-71. https://doi.org/10.1016/j.cmet.2012.01.017
Hochachka PW, Owen TG, Allen JF, Whittow GC. Multiple end products of anaerobiosis in diving vertebrates. Comparative Biochemistry and Physiology. B, Comparative Biochemistry. 1975;50:17-22. https://doi.org/10.1016/0305-0491(75)90292-8
Hohl C, Oestreich R, Rosen P, Wiesner R, Grieshaber M. Evidence for succinate production by reduction of fumarate during hypoxia in isolated adult rat heart cells. Archives of Biochemistry and Biophysics. 1987;259:527-535. https://doi.org/10.1016/0003-9861(87)90519-4
Sanborn T, Gavin W, Berkowitz S, Perille T, Lesch M. Augmented conversion of aspartate and glutamate to succinate during anoxia in rabbit heart. American Journal of Physiology. 1979;237:H535-H541. https://doi.org/10.1152/ajpheart.1979.237.5.H535
Taegtmeyer H. Metabolic responses to cardiac hypoxia. Increased production of succinate by rabbit papillary muscles. Circulation Research. 1978; 43:808-815. https://doi.org/10.1161/01.res.43.5.808
Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, Honore JC, Kermorvant-Duchemin E, Varma DR, Tremblay S. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nature Medicine. 2008;14:1067-1076. https://doi.org/10.1038/nm.1873