Mitochondrial Signaling in Hypoxia


This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance; 2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation; 3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activity. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.

Share and Cite:

L. Lukyanova, "Mitochondrial Signaling in Hypoxia," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 2A, 2013, pp. 20-32. doi: 10.4236/ojemd.2013.32A004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] U. T. Brunk and A. Terman, “The Mitochondrial-Lysosomal Axis Theory of Aging,” European Journal of Biochemistry, Vol. 269, No. 8, 2002, pp. 1996-2002. doi:10.1046/j.1432-1033.2002.02869.x
[2] K. Michiels, “Physiological and Pathological Responses to Hypoxia,” American Journal of Pathology, Vol. 164, No. 6, 2004, pp. 1875-1882. doi:10.1016/S0002-9440(10)63747-9
[3] L. D. Lukyanova , A. M. Dudchenko, E. L. Germanova, T. A. Tsybina, R. A.Kopaladse, I. V. Ehrenbourg and E. N. Tkatchouk, “Mitochondria Signaling in Formation of Body Resistance to Hypoxia,” In: L. Xi and T. Serebrovskaya, Eds., Intermitten Hypoxia: From Molecular Mechanisms to Clinical Applications, Nova Science Publishers, 2009, pp. 423-450.
[4] L. D. Lukyanova, A. M. Dudchenko, T. A. Tsybina, E. L. Germanova, E. N. Tkatchouk and V. Ehrenbourg, “Effect of Intermittent Normobaric Hypoxia on Kinetic Properties of Mitochondrial Enzymes,” Bulletin of Experimental Biology and Medicine, Vol. 144, No. 6, 2007, pp. 795-801. doi:10.1007/s10517-007-0434-y
[5] D. A. Hems and J. T. Brosnan, “Effects of Ischaemia on Content of Metabolites in Rat Liver and Kidney in Vivo,” Biochemical Journal, Vol. 120, 1970, pp. 105-111.
[6] L. D. Lukyanova, “Limiting Steps of Energy Metabolism in Brain in Hypoxia,” Neurochemistry International, Vol. 13, No. 1, 1988, pp. 146-147.
[7] L. D. Lukyanova, “Molecular, Metabolic and Functional Mechanisms of Individual Resistance to Hypoxia,” In: B. K. Sharma, N. Takeda, et al., Eds., Adaptation Biology and Medicine, Vol. I, Narosa Publishing House, New Dehli, 1997, pp. 261-272.
[8] L. D. Lukyanova, “Сellular Mechanism Responsible for Beneficial Effects of Hypoxic Therapy,” In: Moravec, et al., Eds., Adaptation Biology and Medicine, Vol. 3, Narosa Publishing House, New Dehli, 2002, pp. 290-303.
[9] L. D. Lukyanova and A. M. Dudchenko, “Regulatory Role of the Adenylate Pool in the Formation of Hepatocyte Resistance to Hypoxia,” In: K. B. Pandolf, N. Takeda, P. K. Singal, Eds., Adaptation Biology and Medicine, Vol. 2, Narosa Publishing House, New Dehli, 1999, pp. 139-150.
[10] L. D. Lukyanova, E. L. Germanova and Yu. I. Kirova, “The Signal Function of Succinate and Free Radicals in Mechanisms of Preconditioning and Long-term Adaptation to Hypoxia,” In: P. Wang, C.-H. Kuo, N. Takeda and P. K. Singal, Eds., Adaptation Biology and Medicine, Vol. 6, Cell Adaptations and Challenges, Chapter 19, 2011, pp. 251-277.
[11] H. N. Aithal and T. Ramasarma, “Activation of Liver Succinate Dehydrogenase in Rats Exposed to Hypobaric Conditions,” Biochemical Journal, Vol. 115, No. 1, 1969, pp. 77-83.
[12] F. H. Agani, P. Pichiule, J. C. Chavez and J. C. La Manna, “The Role of Mitochondria in the Regulation of Hypoxia-Inducible Factor 1 Expression during Hypoxia,” JBC, Vol. 275, No. 46, 2000, pp. 35863-35867. doi:10.1074/jbc.M005643200
[13] F. H. Agani, M. Puchowicz, J. C. Chavez, P. Pichiule and J. LaManna, “Inhibitors of Mitochondrial Complex I Attenuate the Accumulation of Hypoxia-Inducible Factor-1 during Hypoxia in Hep3B Cells,” Comparative Biochemistry and Physiology, Vol. 132, No. 1, 2000, pp. 107-109.
[14] J. C. Chavez, F. Agani, P. Pichule and J. C. LaManna, “Expression of Hypoxia-Inducible Factor-1a in the Brain of Rats during Chronic Hypoxia,” Journal of Applied Physiology, Vol. 89, No. 5, 2000, pp. 1937-1942.
[15] M. M. Da Silva, F. Sartori, E. Belisle and A. J. Kowaltowsky, “Ischemic Preconditioning Inhibits Mitochondrial Respiration, Increase H2O2 Release, and Enhances K+ Transport,” American Journal of Physiology: Heart and Circulatory Physiology, Vol. 285, 2003, pp. 154-162.
[16] M. I. Genova, R. Casteluccio, G. Fato, M. Parenti-Castelli, G. Merlo-Pich, C. Formiggini, M. Bovina and G. M. Lenaz, “Major Changes in Complex I Activity in Mitochondrian from Aged Rats May Not be Detected by Direct Assay of NADH-Coenzyme Q Reductase,” Biochemical Journal, Vol. 311, 1995, pp. 105-109.
[17] N. D. Goldberg, J. V. Passonneau and O. H. Lowry, “Effects of Changes in Brain Acid Cycle Intermediates,” Journal of Biological Chemistry, Vol. 241, No.17, 1966, pp. 3997-4003.
[18] L. D. Lukyanova, E. L. Germanova, T. A. Tsybina and G. N. Chernobaeva, “Energotropic Effect of Succinate-Containing Derivatives of 3-Hydroxypyridine,” Bulletin of Experimental Biology and Medicine, Vol. 148, No. 4, 2009, pp. 587-591. doi:10.1007/s10517-010-0771-0
[19] E. Maklashinas, E. Sher, H.-Z. Zhou and M. Gray, “Effect of Anoxia/Reperfusion on the Reversible Active/ de-Active Transition of Complex I in Rat Hear,” Bioenergetics, Vol. 1556, No. 1, 2002, pp. 6-12. doi:10.1016/S0005-2728(02)00280-3
[20] L. Mela., C. W. Goodwin and L. D. Miller, “In Vivo Control of Mitochondrial Enzyme Concentrations and Activity by Oxygen,” American Journal of Physiology, Vol. 231, No. 6, 1976, pp. 1811-1816.
[21] S. Pitkanen and B. H. Robinso, “Mitochondrial Complex I Deficiency Leads to Increased Production of Superoxide Radicals and Induction of Superoxide Dismutase,” Journal of Clinical Investigation, Vol. 98, No. 2, 1996, pp. 345-351. doi:10.1172/JCI118798
[22] B. H. Robinson, “Human Comlex I Deficiency: Clinical Spectrum and Involvement of Oxygen Free Radicals in the Pathogenicity of the Defect,” Biochimica et Biophysica Acta, Vol. 1364, No. 2, 1998, pp. 271-286. doi:10.1016/S0005-2728(98)00033-4
[23] W. Rouslin and R. W. Millard, “Canine Myocardial Ischemia: Defect in Mitochondrial Electron Transfer Complex I,” Journal of Molecular and Cellular Cardiology, Vol. 12, No. 6, 1980, pp. 639-645. doi:10.1016/0022-2828(80)90021-8
[24] H. A. Sadek, P. A. Sweda and L. I Sweda, “Modulation of Mitochondrial Complex I Activity by Reversible Ca2+ and NADH Mediated Superoxide Anion Dependent Inhibition,” Biochemistry, Vol. 43, No. 26, 2004, pp. 8494-8502. doi:10.1021/bi049803f
[25] J. M. Weinberg, M. A. Venkatachalm and F. Nancy, “Anaerobic and Aerobic Pathways for Salvage of Ptoximal Tubules from Hypoxia-Induced Mitochondrial Injury,” American Journal of Physiology: Renal Physiology, Vol. 279, 2000, pp. F927-F943.
[26] J. M. Weinberg, M. A. Venkatachalm and F. Nancy, “Mitochondrial Disfunction during Hypoxia/ Reoxigenation and Its Correction by Anaerobic Metabolism of Citric Acid Cycle Intermediates,” Proceedings of the National Academy of Science of USA, Vol. 97, No. 6, 2000, pp. 2826-2831. doi:10.1073/pnas.97.6.2826
[27] P. R. Correa, E. A. Kruglov, M. Thompson, M. F. Leite, J. A. Dranoff and M. H. Nathanson, “Succinate Is a Paracrine Signal for Liver Damage,” Journal of Hepatology, Vol. 47, No. 2, 2007, pp. 262-269. doi:10.1016/j.jhep.2007.03.016
[28] T. Feldkamp, A. Kribben, N. F. Roeser , R. A. Senter, S. Kemner, M. A. Venkatachalam, I. Nissim and J. M. Weinberg, “Preservation of Complex I Function during Hypoxia-Reoxygenation-Induced Mitochondrial Injury in Proximal Tubules,” American Journal of Physiology: Renal Physiology, Vol. 286, No. 4, 2004. pp. 749-759. doi:10.1152/ajprenal.00276.2003
[29] M. Gutman, “Modulation of Mitochondrial Succinate Dehydrogenese Activity, Mechanism and Function,” Molecular and Cellular Biochemistry, Vol. 20, No. 1, 1978, pp. 41-60. doi:10.1007/BF00229453
[30] W. He, F. J. Miao and D. C. Lin, “Citric Acid Cycle Intermediates as Ligands for Orphan-G-Protein-Coupled Receptors,” Nature, Vol. 429, No. 6988, 2004, pp. 188-193. doi:10.1038/nature02488
[31] P. W. Hochachka, T. G. Owen, J. F. Allen and G. C. Whittow, “Multiple End Products of Anaerobiosis in Diving Vertebrates,” Comparative Biochemistry and Physiology, Vol. 50, No. 1, 2001, pp. 17-22.
[32] P. W. Hochachka and G. N. Somero, “Biochemical Adaptation—Mechanism and Process in Physiological Evolution,” Oxford University Press, New York, 2001.
[33] C. Hohl, R. Oestreich, P. R?sen, R. Wiesner and M. Grieshaber, “Evidence for Succinate Production by Reduction of Fumarate during Hypoxia Inisolat Adult Rat Heart Cells,” Archives of Biochemistry and Biophysics, Vol. 259, No. 2, 1987, pp. 527-535. doi:10.1016/0003-9861(87)90519-4
[34] A. King, M. A. Selak and E. Gottlieb, “Succinate Dehydrogenase and Fumarate Hydratase: Linking Mitochondrial Dysfunction and Cancer,” Oncogene, Vol. 25, No. 34, 2006, pp. 4675-4682. doi:10.1038/sj.onc.1209594
[35] M. N. Kondrashova, “The Formation and Utilization of Succinate in Mitochondria as a Control Mechanism of Energization and Energy State of Tissue,” In: B. Chance, Ed., Biological and Biochemical Oscillators, Academy Press, New York, 1993, pp. 373-397.
[36] L. D. Lukyanova , E. L. Germanova and R. A. Kopaladze, “Development of Resistance of an Organism under Various Conditions of Hypoxic Preconditioning: Role of the Hypoxic Period and Reoxygenation,” Bulletin of Experimental Biology and Medicine, Vol. 147, No. 4, 2009, pp. 400-404. doi:10.1007/s10517-009-0529-8
[37] L. D. Lukyanova, Yu. I. Kirova and E. L. Germanova, “Energotropic Effects of Intermittent Hypoxia and a Possibility of Their Optimization by Modulatory Action of Mitochondrial Substrates,” In: L. Xi and T. V. Serebrovskaya, Eds., Intermittent Hypoxia and Human Diseases, Springer, London, 2012, pp. 239-252.
[38] L. Mela, C. W. Goodwin and L. D. Miller, “In Vivo Control of Mitochondrial Enzyme Concentrations and Activity by Oxygen,” The American Journal of Physiology, Vol. 231, No. 6, 1976, pp. 1811-1816.
[39] G. Nowak, G. L. Clifton and D. Bakajsova, “Succinate Ameliorates Energy Deficits and Prevents Dysfunction of Complex I in Injured Renal Proximal Tubular Cells,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 3, 2008, pp. 1155-1162. doi:10.1124/jpet.107.130872
[40] F. Zoccarato, L. Cavallini, S. Bortolami and A. Alexandre, “Succinate Modulation of H2O2 Release at NADH: Ubiquinone Oxidoreductase (Complex I) in Brain Mitochondria,” Biochemical Journal, Vol. 406, No. 1, 2007, pp. 125-129. doi:10.1042/BJ20070215
[41] H. Taegmeyer, “Metabolic Responses to Cardiac Hypoxia. Increased Production of Succinate by Rabbit Papillary Muscles,” Circulation Research, Vol. 43, 1978, pp. 808-815. doi:10.1161/01.RES.43.5.808
[42] N. Sadagopan, S. L. Roberds, T. Major, G. M. Preston, Yu. Y and M. A. Tones, “Circulating Succinate Is Elevated in Rodent Models of Hypertension and Metabolic Disease,” American Journal of Hypertension, Vol. 20, No. 11, 2007, pp.1209-1215.
[43] J. Cascarano, I. Z. Ades and J. D. O'Conner, “Hypoxia: A Succinate-Fumerate Electron Shuttle between Peripheral Cells and Lung,” Journal of Experimental Zoology, Vol. 198, No. 2, 1976, pp. 149-153. doi:10.1002/jez.1401980204
[44] D. A. Hems and J. T. Brosnan, “Effects of Ischaemia on Content of Metabolites in Rat Liver and Kidney in Vivo,” The Biochemical Journal, Vol. 120, No. 1, 1970, pp. 105-111.
[45] T. Sanborn, W. Gavin, S. Berkowitz, T. Perille and M. Lesch, “Augmented Conversion of Aspartate and Glutamate to Succinate during Anoxia in Rabbit Heart,” The American Journal of Physiology, Vol. 237, No. 5, 1979, pp. H535-H541.
[46] I. Toma, J. J. Kang, A. Sipos, S. Vargas, E. Bansal, F. Hanner, E. Meer and J. Peti-Peterdi, “Succinate Receptor GPR91 Provides a Direct Link between High Glucose Levels and Renin Release in Murine and Rabbit Kidney,” The Journal of Clinical Investigation, Vol. 118, No. 7, 2008, pp. 2526-2534.
[47] G. L. Semenza, “Signal Transduction to Hypoxia-Inducible Factor 1,” Biochemical Pharmacology, Vol. 64, No. 5-6, 2002, pp. 993-998. doi:10.1016/S0006-2952(02)01168-1
[48] G. L. Semenza, “Oxygen-Dependent Regulation of Mitochondrial Respiration by Hypoxia-Inducible Factor 1,” The Biochemical Journal, Vol. 405, No. 1, 2007, pp. 1-9.
[49] G. L. Semenza, “Involvement of Oxygen-Sensing Pathways in Physiologic and Pathologic Erythropoiesis,” Blood, Vol. 114, No. 10, 2009, pp. 2015-2019. doi:10.1182/blood-2009-05-189985
[50] G. L. Semenza and G. Wang, “A Nuclear Factor Induced by Hypoxia via de Novo Protein Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation,” Molecular and Cellular Biology, Vol. 12, No. 12, 1992, pp. 5447-5454.
[51] G. Wang and G. L. Semenza, “Characterization of Hypoxia-Inducible Factor 1 and Regulation of DNA Binding Activity by Hypoxia,” The Journal of Biological Chemistry, Vol. 268, No. 29, 1993, pp. 21513-21518.
[52] L. A. Shimoda and G. L. Semenza, “Role of Hypoxia-Inducible Factors in Pulmonary Development and Disease,” American Journal of Respiratory and Critical Care Medicine, Vol. 183, No. 2, 2011, pp. 152-156. doi:10.1164/rccm.201009-1393PP
[53] M. Napolitano, D. Centoze, P. Gubellini, S. Rossi, S. Spiezia, G. Bernardi, F. Gulino and P. Calabresi, “Inhibition of Mitochondrial Complex II Alters Strial Expression of Genes Involved in Glutamatergi Signaling: Possible Implications for Huginton’s Diease,” Neurobiology of Disease, Vol. 15, No. 2, 2004, pp. 407-414. doi:10.1016/j.nbd.2003.11.021
[54] D. M. Stroka, T. Burkhardt and I. Desballerts, “HIF-1 Is Expressed in Normoxia Tissue and Displays an Organ-Specific Regulation under Systemic Hypoxia,” FASEB Journal, Vol. 15, No. 13, 2001, pp. 2445-2453.
[55] K .S. Hewitson, B. M. Lienard, M. A. McDonough, I. J. Clifton, D. Butler, A. S. Soares, N. J. Oldham, L. A. McNeill and C. J. Schofield, “Structural and Mechanistic Studies on the Inhibition of the Hypoxia-Inducible Transcription Factor Hydroxylases by Tricarbonic Acid Cycle Intermediates,” The Journal of Biological Chemistry, Vol. 282, No. 5, 2007, pp. 3293-3230. doi:10.1074/jbc.M608337200
[56] P. Kolvunen, M. Hirsila, A. M. Remes, I. E. Hassinen, K. I. Kivirikko and J. Myllyharju, “Inhibition of Hypoxia-Inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates: Possible Links between Cell Metabolism and Stabilization of HIF,” The Journal of Biological Chemistry, Vol. 282, No. 7, 2007, pp. 4524-4532. doi:10.1074/jbc.M610415200
[57] M. A. Selak, S. M. Armour and E. D. McKenzie, “Succinate Links TCA Cycle Dysfunction to Oncogenesis by Inhibiting HIF-α Prolyl Hydroxylase,” Cancer Cell, Vol. 7, No. 1, 2005, pp. 77-85. doi:10.1016/j.ccr.2004.11.022
[58] E. C. Vaux, E. Metzen, K. M. Yeates, P. J. Ratcliffe, “Regulation of Hypoxia-Inducible Factor Is Reserved in the Absence of a Functioning Respiratory Chain,” Blood, Vol. 98, No. 2, pp. 296-302. doi:10.1182/blood.V98.2.296
[59] J. -W. Kim, I. Tchernyshyov, G. L. Semenza and C. V. Dang, “HIF-1-Mediated Expression of Pyruvate Dehydrogenase Kinase: A Metabolic Switch Required for Cellular Adaptation to Hypoxia,” Cell Metabolism, Vol. 3, No. 3, 2006, pp. 177-185. doi:10.1016/j.cmet.2006.02.002
[60] G. Komaromy-Hiller, P. D. Sundquist, L. J. Jacobsen, K. L. Nuttall, “Serum Succinate by Capillary Zone Electrophoresis: Marker Candidate for Hypoxia,” Annals of Clinical Laboratory Science, Vol. 27, No. 2, 1997, pp. 163-168.
[61] L. Baumbach, P. P. Leyssac, S. l. Skinner, “Studies on Renin Release from Isolated Superfused Glomeruli: Effects of Temperature, Urea, Ouabain and Ethacrynic Acid,” The journal of physiology, Vol. 258, No. 1, 1976. pp.243-256.
[62] R. Paddenberg, B. Ishak, A. Goldenberg, P. Faulhammer, F. Rose, N. Weissmann, R. Braun-Dullaeus and W. Kummer, “Essential Role of Complex II of the Respiraitory Chain in Hypoxia-Induced ROS Generation in Pulmonary Vasculature,” American Journal of Physilogy, Lung Cellular and Molecular Physiology, Vol. 284, 2003, pp. L710-L719.
[63] W. He, F. J. Miao and D. C. Lin, “Citric Acid Cycle Intermediates as Ligands for Orphan-G-Protein-Coupled Receptors,” Nature, Vol. 429, 2004, pp.188-193. doi:10.1038/nature02488
[64] C. Peers and P. J. Kemp, “Acute Oxygen Sensing: Diverse but Convergent Mechanisms in Airway and Arterial Chemoreceptors,” Respiratory Research, Vol. 2, No. 3, 2001, pp. 145-149. doi:10.1186/rr51
[65] Y. Hakak, K. Lehmann-Bruinsma, S. Phillips, Le T. Llaw, D. T. Connolly and D. P. Behan, “The Role of GPR91 Ligand Succinate in Hematopoiesis,” Journal of Leukocyte Biology, Vol. 85, No. 5, 2009, pp. 837-843. doi:10.1189/jlb.1008618
[66] T. Rubic, G. Lametschwandtner, S. Hinteregger and J. Kund, “Triggering the Succinate Receptor GPR91 on Dendritic Cells Enhances Immunity,” Nature Immunology, Vol. 9, No. 11, 2008, pp. 1261-1269.
[67] G. Serviddio, N. Di Venosa, D. Agostino, T. Rollo, F. Priggigalo, E. Altomare and T. Fiore, “Brief Hypoxia before Normoxic Reperfusion (Postconditioning) Protects the Heart against Ischemia-Reperfusion Injury by Preventing Mitochondria Peroxide Production and Glutathion Depletion,” The Journal of the Federation of American Societies for Experimental Biology, Vol. 19, No. 3, 2005, pp. 354-361. doi:10.1096/fj.04-2338com
[68] P. Sapieha, M. Sirinyan, D. Hamel, K. Zaniolo, J. S. Joyal, J. C. Honore, E. Kermorvant-Duchemin and D. R. Varma, “The Succinate Receptor GPR91 in Neurons Has a Major Role in Retinal Angiogenesis,” Nature Medicine, Vol. 14, No. 10, 2008, pp. 1067-1076.
[69] J. B. Regard, I. T. Sato and S. R. Coughlin, “Anatomical Profiling of G Protein-Coupled Receptor Expression,” Cell, Vol. 135, No. 3, 2008, pp. 561-571. doi:10.1016/j.cell.2008.08.040
[70] M. N. Kondrashova and N. M. Doliba, “Polarografiphic Observation of Substrate-Level Phosphorylation and Its Stimulation by Acetylcholine,” FEBS Letters, Vol. 243, No. 2, 1989, pp. 153-155. doi:10.1016/0014-5793(89)80119-X
[71] R. A. Butow and N. G. Avadhani, “Mitochondria Signaling. The Retrograde Response,” Molecular Cell, Vol. 14, No. 1, 2004, pp. 1-15.
[72] E .L. Bell, T. A. Klimova, J. Eisenbart, C. T. Shumacker and N. S. Chandel, “Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia,” Molecular and Cellular Biology, Vol. 27, No. 16, 2007, pp. 5737-5745. doi:10.1128/MCB.02265-06
[73] N. S. Chandel and P. T. Schumacker, “Cellular Oxygen Sensing by Mitochondria: Old Questions, New Insight,” The American Journal of Physiology, Vol. 88, No. 5, 2000, pp. 1880-1889.
[74] J. Das, “The Role of Mitochondrial Respiration in Physiological and Evolutionary Adaptation,” BioEssays, Vol. 28, No. 9, 2006, pp. 890-901. doi:10.1002/bies.20463
[75] M. R. Duchen, “Roles of Mitochondria in Health and Disease,” Diabetes, Vol. 53, No. S1, 2009, pp. S96-S102. doi:10.2337/diabetes.53.2007.S96

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.