zabmedvestnikЗабайкальский медицинский вестникTransbaikalian Medical Bulletin1998-6173Читинская государственная медицинская академия10.52485/19986173_2025_3_85zabmedvestnik-462Research ArticleНАУЧНЫЕ ОБЗОРЫSCIENTIFIC REVIEWSРОЛЬ СУКЦИНАТА В РЕГУЛЯЦИИ МЕТАБОЛИЗМА: ФИЗИОЛОГИЧЕСКИЕ И ПАТОФИЗИОЛОГИЧЕСКИЕ АСПЕКТЫTHE ROLE OF SUCCINATE IN METABOLISM REGULATION: PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTShttps://orcid.org/0000-0001-7544-3779ТепляшинаЕ. А.TeplyashinaE. A.

Тепляшина Елена Анатольевна, к.биол.н., доцент кафедры биологической химии с курсами медицинской, фармацевтической и токсикологической химии

660022, г. Красноярск, ул. Партизана Железняка, 1

Teplyashina E.A., Candidate of Biological Sciences, Associate Professor of the Department of Biological Chemistry with courses in Medical, Pharmaceutical and Toxicological chemistry

1 Partizana Zheleznyaka St., Krasnoyarsk, 660022

elenateplyashina@mail.ruФГБОУ ВО «Красноярский государственный медицинский университет имени профессора В.Ф. Войно-Ясенецкого» Министерства здравоохранения РФРоссияProf. V.F. Voino-Yasenetsky Krasnoyarsk State Medical UniversityRussian Federation202502112025038595Copyright © Тепляшина Е.А., 20252025Тепляшина Е.А.Teplyashina E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.zabmedvestnik.ru/jour/article/view/462

Центральным звеном энергетического метаболизма клетки выступают субстраты и ферменты цикла Кребса, а также электрон-транспортной цепи митохондрий. Метаболиты цикла Кребса присутствуют также в кровотоке и выполняют важные функции, находясь за пределами цикла. Цель настоящего обзора заключается в установлении новых представлений о механизмах действия сукцината при стрессовых ситуациях с учетом механизма субстратного фосфорилирования. Для изучения научных достижений в области энергетического метаболизма использовались такие методы как системно-структурный и сравнительный. Использование обозначенных методов позволило представить авторскую схему, отображающую общие закономерности метаболических изменений сукцината при гипоксии, воспалении и опухолевом росте.На основе имеющихся литературных данных представлены молекулярные механизмы действия сукцината, ассоциированные с развитием патологических состояний. Рассмотрены особенности действия фермента сукцинатдегидрогеназы. Установлено, что энергозависимые процессы доминируют в поддержании функциональных систем организма. Выявлены потенциальные молекулярные маркеры, отражающие реальную ценность в отслеживании динамики патологического процесса.Сформулирован вывод о необходимости дальнейшего изучения роли сукцината в энергетическом гомеостазе клетки как для фундаментальной науки, так и для клинической медицины.

The central link in the cell's energy metabolism are the substrates and enzymes of the Krebs cycle, as well as the electron transport chain of the mitochondria. Metabolites of the Krebs cycle are also present in the bloodstream and perform important functions outside the cycle. The aim of this review is to establish new concepts on the mechanisms of action of succinate in stress situations, taking into account the mechanism of substrate phosphorylation.To study scientific achievements in the field of energy metabolism, such methods as system-structural and comparative were used. The use of the designated methods allowed us to present the author's scheme, displaying the general patterns of metabolic changes in succinate during hypoxia, inflammation and tumor growth.Molecular mechanisms of succinate action associated with the development of pathological conditions have been identified. The features of the action of the enzyme succinate dehydrogenase are considered. It has been established that energy-dependent processes dominate in maintaining the main functional systems of the body. Potential molecular markers that reflect real value in monitoring the dynamics of the pathological process have been identified.A conclusion is formulated about the need for further study of the role of succinate in cellular energy homeostasis for both fundamental science and clinical medicine.

сукцинатсукцинатдегидрогеназаэнергетический обменгипоксиявоспалениеопухолевый ростsuccinatesuccinate dehydrogenaseenergy metabolismhypoxiainflammationtumor growthReferencesMartı́nez-Reyes I., Chandel N. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun. 2020. 11 (1): 102. doi:10.1038/s41467-019-13668-3.Martı́nez-Reyes I., Chandel N. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun. 2020. 11 (1): 102. doi:10.1038/s41467-019-13668-3.Arnold P.K., Finley L.W.S. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem. 2023. 299 (2). 102838. doi: 10.1016/j.jbc.2022.102838.Arnold P.K., Finley L.W.S. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem. 2023. 299 (2).102838. doi: 10.1016/j.jbc.2022.102838.Liu X., Zhao G., Sun S., et al. Biosynthetic Pathway and Metabolic Engineering of Succinic Acid. Front. Bioeng. Biotechnol. 2022. 10. doi: https://doi.org/10.3389/fbioe.2022.843887.Liu X., Zhao G., Sun S., et al. Biosynthetic Pathway and Metabolic Engineering of Succinic Acid. Front. Bioeng. Biotechnol. 2022. 10. doi: https://doi.org/10.3389/fbioe.2022.843887.Zhang W., Lang R. Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer. Front Cell Dev Biol. 2023. 11:1266973. doi: 10.3389/fcell.2023.1266973.Zhang W., Lang R. Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer. Front Cell Dev Biol. 2023. 11: 1266973. doi: 10.3389/fcell.2023.1266973.Ahmed A., Iaconisi G.N., Molfetta D. Di, Coppola A.C., Singh A., Bibi A., Capobianco L., Palmieri L., Dolce V., Fiermonte G. Jnt. J. Mol. Shi. 2025. 26 (1). 92. https://doi.org/10.3390/ijms26010092.Ahmed A., Iaconisi G.N., Molfetta D.Di, Coppola A.C., Singh A., Bibi A., Capobianco L., Palmieri L., Dolce V., Fiermonte G. Jnt. J. Mol. Shi. 2025. 26 (1). 92. https://doi.org/10.3390/ijms26010092.Atallah R., Olschewski A., Heinemann A. Succinate at the crossroad of metabolism and angiogenesis: Roles of SDH, HIF1alpha and SUCNR1. Biomedicines. 2022. 10:3089. doi:10.3390/biomedicines10123089.Atallah R., Olschewski A., Heinemann A. Succinate at the crossroad of metabolism and angiogenesis: Roles of SDH, HIF1alpha and SUCNR1. Biomedicines. 2022. 10: 3089. doi:10.3390/biomedicines10123089.Shichkova P., Coggan J.S., Keller D. Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes. Cells. 2024. 13 (20). 1714. https://doi.org/10.3390/cells13201714.Shichkova P., Coggan J.S., Keller D. Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes. Cells. 2024. 13 (20). 1714. https://doi.org/10.3390/cells13201714.Krzak G., Willis C.M., Smith J.A., Pluchino S., Peruzzoti-Jarmetti L. Succinate receptor 1: an emerging regulator of myeloid cell function in inflammation. Trends Immunol. 2021. 42 (1). 45–58. doi: 10.1016/j.it.2020.11.004.Krzak G., Willis C.M., Smith J.A., Pluchino S., Peruzzoti-Jarmetti L. Succinate receptor 1: an emerging regulator of myeloid cell function in inflammation. Trends Immunol. 2021. 42 (1). 45–58. doi: 10.1016/j.it.2020.11.004.Guo Y., Cho S.W., Saxena D., Li X. Multifaceted Actions of Succinate as a Signaling Transmitter Vary with Its Cellular Locations. Endocrinol Metab. 2020. 35 (1). 36–43. doi: 10.3803/EnM.2020.35.1.36.Guo Y., Cho S.W., Saxena D., Li X. Multifaceted Actions of Succinate as a Signaling Transmitter Vary with Its Cellular Locations. Endocrinol Metab. 2020. 35 (1). 36–43. doi: 10.3803/EnM.2020.35.1.36.Eastin T.M., Dye J.A., Pillai P., et al. Delayed revascularization in acute ischemic stroke patients. Front. Pharmacol. 2023. 14. https://doi.org/10.3389/fphar.2023.1124263.Eastin T.M., Dye J.A., Pillai P., et al. Delayed revascularization in acute ischemic stroke patients. Front. Pharmacol. 2023. 14. https://doi.org/10.3389/fphar.2023.1124263.Эльбекьян К.С., Маркарова Е.В., Унанян Л.С., и соавт. Сукцинатдегидрогеназа как новая мишень для связывания мелатонина в комплексном лечении сахарного диабета // Вестник Российского университета дружбы народов. Серия: Медицина. 2022. Т. 26. № 3. С. 221–231. doi:10.22363/2313-0245-2022-26-3-221-231.Elbekyan K.S., Markarova E.V., Unanyan L.S., et al. Succinate dehydrogenase as a new target for melatonin binding in the complex diabetes mellitus treatment. // RDN Journal of Medicine. 2022. Т. 26. № 3. С. 221–231. doi:10.22363/2313-0245-2022-26-3-221-231. In Russian.Шодиев Д.Р., Звягина В.И., Рябова М.Н., Марсянова Ю.А. Сукцинат-рецепторная система костно-хрящевой ткани у пациентов с метаболическим фенотипом остеоартрита. Вопросы биологической, медицинской и фармацевтической химии. 2024. 27 (4). 42−49. https://doi.org10.29296/25877313-2024-04-06.Shodiev D.R., Zvyagina V.I., Ryabova M.N., Marsyanova Yu.A. Succinate-receptor system of bone and cartilage tissue in patients with metabolic phenotype of osteoarthritis. Problems of biological, medical and pharmaceutical chemistry. 2024. 27 (4). 42−49. https://doi.org10.29296/25877313-2024-04-06. In Russian.Cao K., Xu J., Cao W., et al. Assembly of mitochondrial succinate dehydrogenase in human health and disease. Free Radic Biol Med. 2023. 207. 247–259. doi: 10.1016/j.freeradbiomed.2023.07.023.Cao K., Xu J., Cao W., et al. Assembly of mitochondrial succinate dehydrogenase in human health and disease. Free Radic Biol Med. 2023. 207. 247–259. doi: 10.1016/j.freeradbiomed.2023.07.023.Esteban-Amo M.J., Jimenez-Cuadrado P., Serrano-Lorenzo P. Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme. Biomedicines. 2024. 12 (9). 2050. doi: 10.3390/biomedicines12092050.Esteban-Amo M.J., Jimenez-Cuadrado P., Serrano-Lorenzo P. Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme. Biomedicines. 2024. 12 (9). 2050. doi: 10.3390/biomedicines12092050.Wang Q., Li M., Zhou Y., Zhou Y., Yan J. Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease. Exp Biol Med. 2023. 248 (3). 263–270. doi: 10.1177/15353702221147567.Wang Q., Li M., Zhou Y., Zhou Y., Yan J. Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease. Exp Biol Med. 2023. 248 (3). 263–270. doi: 10.1177/15353702221147567.Moosavi B., Berry E.A., Zhu X.L., Yang W.-C., Yang G.-Fu The assembly of succinate dehydrogenase: a key enzyme in bioenergetics. Cell Mol Life Sci. 2019. 76 (20). 4023–4042. doi: 10.1007/s00018-019-03200-7.Moosavi B., Berry E.A., Zhu X.L., Yang W.-C., Yang G.-Fu The assembly of succinate dehydrogenase: a key enzyme in bioenergetics. Cell Mol Life Sci. 2019. 76 (20). 4023–4042. doi: 10.1007/s00018-019-03200-7.Benit P., Goncalves J., Knoury R.El., et al. Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad. Biomedicine. 2022. 10 (8). 1788. doi.org/10.3390/biomedicines10081788.Benit P., Goncalves J., Knoury R.El., et al. Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad. Biomedicine. 2022. 10 (8). 1788. doi.org/10.3390/biomedicines10081788.Hou X., Chen Y., Li X., et al. Protein succinylation: regulating metabolism and beyond. Front Nutr. 2024. 11. 1336057. doi: 10.3389/fnut.2024.1336057.Hou X., Chen Y., Li X., et al. Protein succinylation: regulating metabolism and beyond. Front Nutr. 2024. 11. 1336057. doi: 10.3389/fnut.2024.1336057.Mu R., Ma Z., Lu C., et al. Role of succinylation modification in thyroid cancer and breast cancer. Am J Cancer Res. 2021. 11 (10) : 4683–4699.Mu R., Ma Z., Lu C., et al. Role of succinylation modification in thyroid cancer and breast cancer. Am J Cancer Res. 2021. 11 (10):4683–4699.Yang Y., Tapias V., Acosta D., et al. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease. Nat Commun. 2022. 13 : 159. doi: 10.1038/s41467-021-27572-2.Yang Y., Tapias V., Acosta D., Xu H., Chen H., Bhawal R. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease. Nat Commun. 2022. 13: 159. doi: 10.1038/s41467-021-27572-2.Huang L.Y., Ma J.-Y., Song J.-X., et al. Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion. Neural Regen Res. 2022. 18 (5). 1040–1045. doi: 10.4103/1673-5374.355821.Huang L.Y., Ma J.-Y., Song J.-X., et al. Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion. Neural Regen Res. 2022. 18 (5). 1040–1045. doi: 10.4103/1673-5374.355821.Zhang J., Han Zi-Q., Wang Y., He Q.-Yu Alteration of mitochondrial protein succinylation against cellular oxidative stress in cancer. Mil Med Res. 2022. 9:6. doi: 10.1186/s40779-022-00367-2.Zhang J., Han Zi-Q., Wang Y., He Q.-Yu Alteration of mitochondrial protein succinylation against cellular oxidative stress in cancer. Mil Med Res. 2022. 9: 6. doi: 10.1186/s40779-022-00367-2.Wu Q.J., Zhang T.N., Chen H.H., et al. Zheng G. The sirtuin family in health and disease. Curr. Opin. Chem. Biol. 2019. 51. 18–29. doi:10.1016/j.cbpa.2019.01.023.Wu Q.J., Zhang T.N., Chen H.H., et al. The sirtuin family in health and disease. Curr. Opin. Chem. Biol. 2019. 51. 18–29. doi:10.1016/j.cbpa.2019.01.023.Yang Y., Tapias V., Acosta D., et al. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease. Nat. Commun. 2022. 13. 159. doi: 10.1038/s41467-021-27572-2.Yang Y., Tapias V., Acosta D., et al. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease. Nat. Commun. 2022. 13. 159. doi: 10.1038/s41467-021-27572-2.Kosciuk T., Wang M., Hong J.Y., Lin H. Updates on the epigenetic roles of sirtuins. Curr. Opin. Chem. Biol. 2019. 5. 18–29. doi:10.1016/j.cbpa.2019.01.023.Kosciuk T., Wang M., Hong J.Y., Lin H. Updates on the epigenetic roles of sirtuins. Curr. Opin. Chem. Biol. 2019. 5. 18–29. doi:10.1016/j.cbpa.2019.01.023.Chen C., Zhou M., Ge Y., Wang X. SIRT1 and aging related signaling pathways. Mech. Ageing Dev. 2020. 187. doi: 10.1016/j.mad.2020.11.Chen C., Zhou M., Ge Y., Wang X. SIRT1 and aging related signaling pathways. Mech. Ageing Dev. 2020. 187. doi: 10.1016/j.mad.2020.11.Pande S., Raisuddin S. Molecular and cellular regulatory roles of sirtuin protein. Signal Transduct. Target. Ther. 2022. 7. 402. doi: 10.1038/s41392-022-01257-8.Pande S., Raisuddin S. Molecular and cellular regulatory roles of sirtuin protein. Signal Transduct. Target. Ther. 2022. 7. 402. doi: 10.1038/s41392-022-01257-8.Yang L., Ma X., He Y., et al. Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci. China Life Sci. 2017. 60 (3). 249–256. doi:10.1007/s11427-016-0060-7.Yang L., Ma X., He Y., et al. Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci. China Life Sci. 2017. 60 (3). 249–256. doi:10.1007/s11427-016-0060-7.Ke Z., Shen K., Wang Li, et al. Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development. Front. Immunol. 2025. 16. doi.org/10.3389/fimmu.2025.1531246.Ke Z., Shen K., Wang Li, et al. Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development. Front. Immunol. 2025. 16. doi.org/10.3389/fimmu.2025.1531246.Marquez J., Flores J., Kim, et al. Rescue of TCA Cycle Dysfunction for Cancer Therapy. J Clin Med. 2019. 8 (12). 2161. doi: 10.3390/jcm8122161.Marquez J., Flores J., Kim, et al. Rescue of TCA Cycle Dysfunction for Cancer Therapy. J Clin Med. 2019. 8 (12). 2161. doi: 10.3390/jcm8122161.Chen P.-S., Chiu W.-T., Hsu P.-L., et al. Pathophysiological implications of hypoxia in human diseases. J Biomed Sci. 2020. 27: 63: doi: 10.1186/s12929-020-00658-7.Chen P.-S., Chiu W.-T., Hsu P.-L., et al. Pathophysiological implications of hypoxia in human diseases. J Biomed Sci. 2020. 27: 63: doi: 10.1186/s12929-020-00658-7.Laird M., Ku J.C., Raiten J., et al. Mitochondrial metabolism regulation and epigenetics in hypoxia. Frontiers in Physiology. 2024. 15. https://doi.org/10.3389/fphys.2024.1393232.Laird M., Ku J.C., Raiten J., et al. Mitochondrial metabolism regulation and epigenetics in hypoxia. Frontiers in Physiology. 2024. 15. https://doi.org/10.3389/fphys.2024.1393232.Zong Y., Liao P., Chen L., et al. Mitochondrial dysfunction: mechanism and advances in therapy. Signal Transduction and targeted therapy. 2024. 9. 124. https://doi.org/10.1038/s41392-024-01839-8.Zong Y., Liao P., Chen L., et al. Mitochondrial dysfunction: mechanism and advances in therapy. Signal Transduction and targeted therapy. 2024. 9. 124. https://doi.org/10.1038/s41392-024-01839-8.Huang H., Li G., He Y., et al. Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention. Front. Immunol. 2024. 15. 1–13. doi: 10.3389/fimmu.2024.1404441.Huang H., Li G., He Y., et al. Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention. Front. Immunol. 2024. 15. 1–13. doi: 10.3389/fimmu.2024.1404441.Dambrova M., Zuurbier C.J., Borutaite V., Liepinsh E., Makrecka-Kuka M. 2021. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic. Biol. Med. 2021. 165. 24–37. 10.1016/j.freeradbiomed.2021.01.036.Dambrova M., Zuurbier C. J., Borutaite V., Liepinsh E., Makrecka-Kuka M. 2021. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic. Biol. Med. 2021. 165. 24–37. 10.1016/j.freeradbiomed.2021.01.036.Eniafe J., Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene. 2021. 40 (19). 3351–3363. doi: 10.1038/s41388-020-01639-8.Eniafe J., Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene. 2021. 40(19). 3351–3363. doi: 10.1038/s41388-020-01639-8.Kim H.-J., Kim H., Lee J.-H., Hwangbo C. Toll-like receptor 4 (TLR4): new insight immune and aging. Immun. Ageing. 2023. 20 (67). doi: 10.1186/s12979-023-00383-3.Kim H.-J., Kim H., Lee J.-H., Hwangbo C. Toll-like receptor 4 (TLR4): new insight immune and aging. Immun. Ageing. 2023. 20 (67). doi: 10.1186/s12979-023-00383-3.Huang X., Zhao L., Peng R. Hypoxia-inducible factor 1 and mitochondria: an intimate connection. Biomolecules. 13 (1). 50. doi:10.3390/biom13010050.Huang X., Zhao L., Peng R. Hypoxia-inducible factor 1 and mitochondria: an intimate connection. Biomolecules. 13 (1). 50. doi:10.3390/biom13010050.

The authors declare that there are no conflicts of interest present.