БИОХИМИЯ, 2020, том 85, вып. 1, с. 49–63

УДК 577.121.7

Внутриклеточные механизмы чувствительности к кислороду

Обзор

© 2020 А.Н. Вётош 1,2,3

Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН, 194223 Санкт-Петербург, Россия; электронная почта: vjotnn@yahoo.com

НГУ физической культуры, спорта и здоровья им. П.Ф. Лесгафта, 190121 Санкт-Петербург, Россия

СЗГМУ им. И.И. Мечникова Минздрава России, 195067 Санкт-Петербург, Россия

Поступила в редакцию 09.05.2019
После доработки 29.09.2019
Принята к публикации 20.10.2019

DOI: 10.31857/S0320972520010042

КЛЮЧЕВЫЕ СЛОВА: митохондрии, калиевые мембранные каналы, HIF.

Аннотация

На основании анализа данных литературы описаны молекулярные механизмы рецепции уровня кислорода в различных компартментах клеток животных. Показано, что внутриклеточная сенсорная трансдукция кислорода может осуществляться несколькими способами. Рассмотрены детали функционирования околомембранного и цитоплазматического пулов молекулярных конструктов клеток в условиях гипоксии. Обсуждаются сведения о роли митохондрий в процессах клеточной чувствительности к уменьшению содержания кислорода. Выявлены подробности взаимного влияния оперативных и хронических внутриклеточных механизмов восприятия отрицательных градиентов концентрации молекулярного кислорода и их связи с реакциями клеточного метаболизма на оксидативный стресс.

Благодарности

Автор выражает благодарность Л.Б. Буравковой за полезные и конструктивные обсуждения в ходе выполнения работы.

Конфликт интересов

Автор заявляет об отсутствии конфликта интересов в финансовой или какой-либо иной сфере.

Соблюдение этических норм

Настоящий обзор не содержит описания выполненных автором исследований с участием людей или использованием животных в качестве объектов.

Список литературы

1. Lopez-Barneo, J., Lopez-Lopez, J., Urena, J., and Gonzalez, C. (1988) Chemotransduction in the carotid body: K+ current modulated by PO2 in type I chemoreceptor cells, Science, 241, 580–582.

2. Semenza, G., and Wang, G. (1992) 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, Mol. Cell. Biol., 12, 5447–5454.

3. Semenza, G., Roth, P., Fang, H., and Wang, G. (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1, J. Biol. Chem., 269, 23757–23763.

4. McElroy, G., and Chandel, N. (2017) Mitochondria control acute and chronic responses to hypoxia, Exp. Cell Res., 356, 217–222, doi: 10.1016/j.yexcr.2017.03.034.

5. Скулачев В.П., Богачев А.В., Каспаринский Ф.О. (2010) Мембранная биоэнергетика, Изд-во МГУ, Москва.

6. Waypa, G., Smith, K., and Schumacher, P. (2016) O2 sensing, mitochondria and ROS signaling: the fog is lifting, Mol. Aspects Med., 47–48, 76–89, doi: 10.1016/j.mam.2016.01.002.

7. Santore, M., McClintock, D., Lee, V., Budinger, G., and Chandel, N. (2002) Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells, Am. J. Physiol. Lung Cell. Mol. Physiol., 282, L727–L734, doi: 10.1152/ajplung.00281.2001.

8. Solaini, G., Baracca, A., Lenaz, G., and Sgarbi, G. (2010) Hypoxia and mitochondrial oxidative metabolism, Biochim. Biophys. Acta., 1797, 1171–1177, doi: 10.1016/j.bbabio.2010.02.011.

9. Bell, E., and Chandel, N. (2007) Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species, Essays Biochem., 43, 17–27, doi: 10.1042/BSE0430017.

10. Hamanaka, R., and Chandel, N. (2009) Mitochondrial reactive oxygen species regulate hypoxic signaling, Curr. Opin. Cell Biol., 21, 894–899, doi: 10.1016/j.ceb.2009.08.005.

11. Atkinson, D. (1968) The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers, Biochemistry, 7, 4030–4034.

12. Koo, Y., Cao, Y., Kopelman, R., Koo, S., Brasuel, M., and Philbert, M. (2004) Real-time measurements of dissolved oxygen inside live cells by organically modified silicate fluorescent nanosensors, Anal. Chem., 76, 2498–2505, doi: 10.1021/ac035493f.

13. Mik, E., Stap, J., Sinaasappel, M., Beek, J., Aten, J., van Leeuwen, T., and Ince, C. (2006) Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX, Nat. Methods, 3, 939–945, doi: 10.1038/nmeth940.

14. Быстрова М.Ф., Буданова Е.Н. (2007) Перекись водорода и пероксиредоксины в редокс-регуляции внутриклеточной сигнализации, Биологические мембраны, 24, 115–125.

15. Октябрьский О.Н., Смирнова Г.В. (2007) Редокс-регуляция клеточных функций, Биохимия, 72, 158–174.

16. Hopkins, B.L., and Neumann, C.A. (2019) Redoxins as gatekeepers of the transcriptional oxidative stress response, Redox Biol., 21, 101–104, doi: 10.1016/j.redox.2019.101104.

17. Quinlan, C., Perevoshchikova, I., Hey-Mogensen, M., Orr, A., and Brand, M. (2013) Sites of reactive oxygen species generation by mitochondria oxidizing different substrates, Redox. Biol., 23, 304–312, doi: 10.1016/j.redox.2013.04.005.

18. Goncalves, R., Bunik, V., and Brand, M. (2016) Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex, Free Radic. Biol. Med., 91, 247–255, doi: 10.1016/j.freeradbiomed.2015.12.020.

19. Sena, L., and Chandel, N. (2012) Physiological roles of mitochondrial reactive oxygen species, Mol. Cell, 48, 158–167, doi: 10.1016/j.molcel.2012.09.025.

20. McCord, J. (1985) Oxygen-derived free radicals in postischemic tissue injury, New Engl. J. Med., 312, 159–163, doi: 10.1056/NEJM198501173120305.

21. Cross, C., Halliwell, B., Borish, E., Pryor, W., Ames, B., Saul, R., McCord, J., and Harman, D. (1987) Oxygen radicals and human disease, Ann. Intern. Med., 107, 526–545.

22. Archer, S., Peterson, D., Nelson, D., DeMaster, E., Kelly, B., Eaton, J., and Weir, E. (1989) Oxygen radicals and antioxidant enzymes alter pulmonary vascular reactivity in the rat lung, J. Appl. Physiol., 66, 102–111, doi: 10.1152/jappl.1989.66.1.102.

23. Michelakis, E., Archer, S., and Weir, E. (1995) Acute hypoxic pulmonary vasoconstriction: a model of oxygen sensing, Physiol. Res., 44, 361–367.

24. Chandel, N., McClintock, D., Feliciano, C., Wood, T., Melendez, J., Rodriguez, A., and Schumacker, P. (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing, J. Biol. Chem., 275, 25130–25138, doi: 10.1074/jbc.M001914200.

25. Waypa, G., Marks, J., Mack, M., Boriboun, C., Mungai, P., and Schumacker, P. (2000) Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes, Circ. Res., 91, 719–726.

26. Guzy, R., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K., Simon, M., Hammerling, U., and Schumacker, P. (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab., 1, 401–408, doi: 10.1016/j.cmet.2005.05.001.

27. Mansfield, K., Guzy, R., Pan, Y., Young, R., Cash, T., Schumacker, P., and Simon, M. (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation, Cell Metab., 1, 393–399, doi: 10.1016/j.cmet.2005.05.003.

28. Lebuffe, G., Schumacker, P., Shao, Z., Anderson, T., Iwase, H., and Vanden Hoek, T.L. (2003) ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel, Am. J. Physiol. Heart Circ. Physiol., 284, H299–H308, doi: 10.1152/ajpheart.00706.2002.

29. Guzy, R., Mack, M., and Schumacker, P. (2007) Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeast, Antioxid. Redox Signal., 9, 1317–1328, doi: 10.1089/ars.2007.1708.

30. Boveris, A., and Cadenas, E. (2000) Mitochondrial production of hydrogen peroxide regulation by nitric oxide and the role of ubisemiquinone, IUBMB Life, 50, 245–250, doi: 10.1080/713803732.

31. Sabharwal, S., and Schumacker, P. (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer, 14, 709–721, doi: 10.1038/nrc3803.

32. Waypa, G., Marks, J., Guzy, R., Mungai, P., Schriewer, J., Dokic, D., and Schumacher P. (2010) Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells, Circ. Res., 106, 526–535, doi: 10.1161/CIRCRESAHA.109.206334.

33. Brand, M. (2016) Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling, Free Radic. Biol. Med., 100, 14–31, doi: 10.1016/j.freeradbiomed.2016.04.001.

34. Remington, S. (2006) Fluorescent proteins: maturation, photochemistry and photophysics, Curr. Opin. Struct. Biol., 16, 714–721, doi: 10.1016/j.sbi.2006.10.001.

35. Liu, H., Colavitti, R., Rovira, I., and Finkel, T. (2005) Redox-dependent transcriptional regulation, Circ. Res., 97, 967–974, doi: 10.1161/01.RES.0000188210.72062.10.

36. Pan, Y., Mansfield, K., Bertozzi, C., Rudenko, V., Chan, D., Giaccia, A., and Simon, M. (2007) Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro, Mol. Cell. Biol., 27, 912–925, doi: 10.1128/MCB.01223-06.

37. Finkel, T. (2012) Signal transduction by mitochondrial oxidants, J. Biol. Chem., 287, 4434–4440, doi: 10.1074/jbc.R111.271999.

38. Bell, E., and Chandel, N. (2007) Genetics of mitochondrial electron transport chain in regulating oxygen sensing, Methods Enzymol., 435, 447–461, doi: 10.1016/S0076-6879(07)35023-4.

39. Orr, A., Vargas, L., Turk, C., Baaten, J., Matzen, J., Dardov, V., Attle, S., Li, J., Quackenbush, D., Goncalves, R., Perevoshchikova, I., Petrassi, H., Meeusen, S., Ainscow, E., and Brand, M. (2015) Suppressors of superoxide production from mitochondrial complex III, Nat. Chem. Biol., 11, 834–836, doi: 10.1038/nchembio.1910.

40. Sabharwal, S., Waypa, G., Marks, J., and Schumacker, P. (2013) Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signaling, Biochem. J., 456, 337–346, doi: 10.1042/BJ20130740.

41. Murphy, M. (2009) How mitochondria produce reactive oxygen species, Biochem. J., 417, 1–13, doi: 10.1042/BJ20081386.

42. Murphy, M., Holmgren, A., Larsson, N., Halliwell, B., Chang, C., Kalyanaraman, B., Rhee, S., Thornalley, P., Partridge, L., Gems, D., Nyström, T., Belousov, V., Schumacker, P., and Winterbourn, C. (2011) Unraveling the biological roles of reactive oxygen species, Cell Metab., 13, 361–366, doi: 10.1016/j.cmet.2011.03.010.

43. Semenza, G. (2012) Hypoxia-inducible factors in physiology and medicine, Cell, 148, 399–408, doi: 10.1016/j.cell.2012.01.021.

44. Rhee, S., Woo, H., Kil, I., and Bae, S. (2012) Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides, J. Biol. Chem., 287, 4403–4410, doi: 10.1074/jbc.R111.283432.

45. Chowdhury, R., Flashman, E., Mecinović, J., Kramer, H., Kessler, B., Frapart, Y., Boucher, J., Clifton, I., McDonough, M., and Schofield, C. (2011) Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1), J. Mol. Biol., 410, 268–279, doi: 10.1016/j.jmb.2011.04.075.

46. Льюин Б. (2016) В кн. Клетки по Льюину (под ред. Кассимерис Л., Лингаппа В., Плоппер Д.), Лаборатория знаний, Москва, с. 26–27.

47. Hoshi, T., and Lahiri, S. (2004) Cell biology. Oxygen sensing: it’s a gas! Cell Biol., 306, 2050–2051, doi: 10.1126/science.1107069.

48. Haddad, G., and Jiang, C. (1997) O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels, Annual Rev. Physiol., 59, 23–42, doi: 10.1146/annurev.physiol.59.1.23.

49. Kemp, P., and Peers. C (2007) Oxygen sensing by ion channels, Essays Biochem., 43, 77–90, doi: 10.1042/BSE0430077.

50. Platoshyn, O., Brevnova, E., Burg, E., Yu, Y., Remillard, C., and Yuan, J. (2006) Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells, Am. J. Physiol. Cell Physiol., 290, C907–C916, doi: 10.1152/ajpcell.00028.2005.

51. Prabhakar, N.R., and Peers, C. (2014) Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body, Physiology (Bethesda), 29, 49–57, doi: 10.1152/physiol.00034.2013.

52. Peers, C., Wyatt, C., and Evans, A. (2010) Mechanisms for acute oxygen sensing in the carotid body, Respir. Physiol. Neurobiol., 174, 292–298, doi: 10.1016/j.resp.2010.08.010.

53. Kemp, P. (2006) Detecting acute changes in oxygen: will the real sensor please stand up? Exp. Physiol., 91, 829–834, doi: 10.1113/expphysiol.2006.034587.

54. Ward, J. (2008) Oxygen sensors in context, Biochim. Biophys. Acta, 1777, 1–14, doi: 10.1016/j.bbabio.2007.10.010.

55. Williams, S., Wootton, P., Mason, H., Bould, J., Iles, D., Riccardi, D., Peers, C., and Kemp, P. (2004) Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel, Science, 306, 2093–2097, doi: 10.1126/science.1105010.

56. Hou, S., Heinemann, S., and Hoshi, T. (2009) Modulation of BKCa channel gating by endogenous signaling molecules, Physiology (Bethesda), 24, 26–35, doi: 10.1152/physiol.00032.2008.

57. Peng, Y., Nanduri, J., Raghuraman, G., Souvannakitti, D., Gadalla, M., Kumar, G., Snyder, S., and Prabhakar, N. (2010) H2S mediates O2 sensing in the carotid body, Proc. Natl. Acad. Sci. USA, 107, 10719–10724, doi: 10.1073/pnas.1005866107.

58. Li, Q., Sun, B., Wang, X., Jin, Z., Zhou, Y., Dong, L., Jiang, L., and Rong, W. (2010) A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-activated potassium channels, Antioxid. Redox Signal., 12, 1179–1189, doi: 10.1089/ars.2009.2926.

59. Peers, C. (2015) Acute oxygen sensing-inching ever closer to an elusive mechanism, Cell Metab., 22, 753–754, doi: 10.1016/j.cmet.2015.10.011.

60. Julius, D., and Nathans, J. (2012) Signaling by sensory receptors, Cold Spring Harb. Perspect. Biol., 4, a005991, doi: 10.1101/cshperspect.a005991.

61. Maines, M. (1997) The heme oxygenase system: a regulator of second messenger gases, Annu. Rev. Pharmacol. Toxicol., 37, 517–554.

62. Prabhakar, N., Dinerman, J., Agani, F., and Snyder, S. (1995) Carbon monoxide: a role in carotid body chemoreception, Proc. Natl. Acad. Sci. USA, 92, 1994–1997.

63. Prabhakar, N. (2012) Carbon monoxide (CO) and hydrogen sulfide (H2S) in hypoxic sensing by the carotid body, Respir. Physiol. Neurobiol., 184, 165–169, doi: 10.1016/j.resp.2012.05.022.

64. Barbé, C., Al-Hashem, F., Conway, A., Dubuis, E., Vandier, C., and Kumar, P. (2002) A possible dual site of action for carbon monoxide-mediated chemoexcitation in the rat carotid body, J. Physiol., 543, 933–945, doi: 10.1113/jphysiol.2001.015750.

65. Lloyd, B., Cunningham, D., and Goode, R. (2013) in Arterial Chemoreceptors (Torrance, R., ed.), Blackwell, Oxford, pp. 145–150.

66. Gadalla, M., and Snyder, S. (2010) Hydrogen sulfide as a gasotransmitter, J. Neurochem., 113, 14–26, doi: 10.1111/j.1471-4159.2010.06580.x.

67. Wang, R. (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed, Physiol. Rev., 92, 791–896, doi: 10.1152/physrev.00017.2011.

68. Mkrtchian, S., Kåhlin, J., Ebberyd, A., Gonzalez, C., Sanchez, D., Balbir, A., Kostuk, E., Shirahata, M., Fagerlund, M., and Eriksson, L. (2012) The human carotid body transcriptome with focus on oxygen sensing and inflammation – a comparative analysis, J. Physiol., 590, 3807–3819, doi: 10.1113/jphysiol.2012.231084.

69. Makarenko, V., Nanduri, J., Raghuraman, G., Fox, A., Gadalla, M., Kumar, G., Snyder, S., and Prabhakarn, N. (2012) Endogenous H2S is required for hypoxic sensing by carotid body glomus cells, Am. J. Physiol. Cell Physiol., 303, C916–C923, doi: 10.1152/ajpcell.00100.2012.

70. Buckler, K. (2012) Effects of exogenous hydrogen sulphide on calcium signalling, background (TASK) K channel activity and mitochondrial function in chemoreceptor cells, Pflug. Arch., 463, 743–754, doi: 10.1007/s00424-012-1089-8.

71. Haouzi, P., Bell, H., and Van de Louw, A. (2011) Hypoxia-induced arterial chemoreceptor stimulation and hydrogen sulfide: too much or too little? Respir. Physiol. Neurobiol., 179, 97–102, doi: 10.1016/j.resp.2011.09.009.

72. Olson, K., and Whitfield, N. (2010) Hydrogen sulfide and oxygen sensing in the cardiovascular system, Antioxid. Redox Signal., 12, 1219–1234, doi: 10.1089/ars.2009.2921.

73. Campanucci, V., and Nurse, C. (2007) Autonomic innervation of the carotid body: role in efferent inhibition, Respir. Physiol. Neurobiol., 157, 83–92, doi: 10.1016/j.resp.2007.01.020.

74. Prabhakar, N., Kumar, G., Chang, C., Agani, F., and Haxhiu, M. (1993) Nitric oxide in the sensory function of the carotid body, Brain Res., 625, 16–22.

75. Silva, J., and Lewis, D. (2002) Nitric oxide enhances Ca(2+)-dependent K(+) channel activity in rat carotid body cells, Pflugers Arch., 443, 671–675, doi: 10.1007/s00424-001-0745-1.

76. Summers, B., Overholt, J., and Prabhakar, N. (1999) Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism, J. Neurophysiol., 81, 1449–1457, doi: 10.1152/jn.1999.81.4.1449.

77. Li, Y., Zheng, H., Ding, Y., and Schultz, H. (2010) Expression of neuronal nitric oxide synthase in rabbit carotid body glomus cells regulates large-conductance Ca2+-activated potassium currents, J. Neurophysiol., 103, 3027–3033, doi: 10.1152/jn.01138.2009.

78. Campanucci, V., Zhang, M., Vollmer, C., and Nurse, C. (2006) Expression of multiple P2X receptors by glossopharyngeal neurons projecting to rat carotid body O2-chemoreceptors: role in nitric oxide-mediated efferent inhibition, J. Neurosci., 26, 9482–9493, doi: 10.1523/JNEUROSCI.1672-06.2006.

79. Колесникова Е.Э. (2004) Молекулярные механизмы рецепции уровня кислорода, Нейрофизиология, 36, 330–347.

80. Samanta, D., Prabhakar, N., and Semenza, G. (2017) Systems biology of oxygen homeostasis, Wiley Interdiscip. Rev. Syst. Biol. Med., 9, e1382, doi: 10.1002/wsbm.1382.

81. Semenza, G. (2010) Oxygen homeostasis, Wiley Interdiscip. Rev. Syst. Biol. Med., 2, 336–361, doi: 10.1002/wsbm.69.

82. Szewczak, L. (2016) Timeline: cellular oxygen sensing, Cell, 167, 286, doi: 10.1016/j.cell.2016.08.065.

83. Lin, F., Suggs, S., Lin, C., Browne, J., Smalling, R., Egrie, J., Chen, K., Fox, G., Martin, F., and Stabinsky, Z. (1985) Cloning and expression of the human erythropoietin gene, Proc. Natl. Acad. Sci. USA, 82, 7580–7584.

84. Bishop, T., and Ratcliffe, P. (2014) Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives, Hypoxia (Auckl), 2, 197–213, doi: 10.2147/HP.S47598.

85. Gleadle, J. (2009) Review article: How cells sense oxygen: lessons from and for the kidney, Nephrology (Carlton), 1, 86–93, doi: 10.1111/j.1440-1797.2008.01064.x.

86. Анохина Е.Б., Буравкова Л.Б. (2010) Механизмы регуляции транскрипционного фактора при гипоксии, Биохимия, 75, 185–195.

87. Masson, N., Willam, C., Maxwell, P., and Pugh, C. (2001) Ratcliffe, P. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation, EMBO J., 20, 5197–5206, doi: 10.1093/emboj/20.18.5197.

88. Maxwell, P., Wiesener, M., Chang, G., Clifford, S., Vaux, E., Cockman, M., Wykoff, C., Pugh, C., Maher, E., and Ratcliffe, P. (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis, Nature, 399, 271–275, doi: 10.1038/20459.

89. Semenza, G. (2016) Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors, Mol. Aspects Med., 47–48, 15–23, doi: 10.1016/j.mam.2015.09.004.

90. Prabhakar, N., and Semenza, G. (2016) Regulation of carotid body oxygen sensing by hypoxia-inducible factors, Pflug. Arch., 468, 71–75, doi: 10.1007/s00424-015-1719-z.

91. Hirsilä, M., Koivunen, P., Günzler, V., Kivirikko, K., and Myllyharju, J. (2003) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor, J. Biol. Chem., 278, 30772–30780, doi: 10.1074/jbc.M304982200.

92. Maltepe, E., Schmidt, J., Baunoch, D., Bradfield, C., and Simon, M. (1997) Abnormal Angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT, Nature, 386, 403–407, doi: 10.1038/386403a0.

93. Townley-Tilson, W., Pi, X., and Xie, L. (2015) The role of oxygen sensors, hydroxylases, and HIF in cardiac function and disease, Oxid. Med. Cell. Longev., 2015, 676893, doi: 10.1155/2015/676893.

94. Epstein, A., Gleadle, J., McNeill, L., Hewitson, K., O’Rourke, J., Mole, D., Mukherji, M., Metzen, E., Wilson, M., Dhanda, A., Tian, Y., Masson, N., Hamilton, D., Jaakkola, P., Barstead, R., Hodgkin, J., Maxwell, P., Pugh, C., Schofield, C., and Ratcliffe, P. (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell, 107, 43–54.

95. Coleman, M.L., and Ratcliffe, P.J. (2007) in Essays in Biochemistry. Oxygen Sensing and Hypoxia-Induced Responses, (Peers. C., ed.), Portland Press, London, pp. 1–15.

96. Тренделева Т.А., Аливердиева Д.А., Звягильская Р.А. (2014) Механизмы определения низкого уровня кислорода у млекопитающих и дрожжей и их адаптационные ответы, Биохимия, 79, 944–956.

97. Погодина М.В., Буравкова Л.Б. (2015) Особенности экспрессии HIF-1α в мультипотентных мезенхимных стромальных клетках при гипоксии, Бюлл. эксп. биол. мед., 159, 333–335.

98. Ivan, M., and Kaelin, W.G. Jr., (2017) The EGLN-HIF O2-sensing system: multiple inputs and feedbacks, Mol. Cell, 66, 772–779, doi: 10.1016/j.molcel.2017.06.002.

99. Kim, J., Tchernyshyov, I., Semenza, G., and Dang, C. (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia, Cell Metab., 3, 177–1785, doi: 10.1016/j.cmet.2006.02.002.

100. Goda N., and Kanai M. (2012) Hypoxia-inducible factors and their roles in energy metabolism, Int. J. Hematol., 95, 457–463, doi: 10.1007/s12185-012-1069-y.

101. Lu, H., Samanta, D., Xiang, L., Zhang, H., Hu, H., Chen, I, Bullen, J., and Semenza, G. (2015) Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype, Proc. Natl. Acad. Sci. USA, 112, E4600–E4609, doi: 10.1073/pnas.1513433112.

102. Gao, L., González-Rodriguez, P., Ortega-Sáenz, P., and López-Barneo, J. (2017) Redox signaling in acute oxygen sensing, Redox Biol., 12, 908–915, doi: 10.1016/j.redox.2017.04.033.

103. Fernández-Agüera, M., Gao, L., González-Rodriguez, P., Pintado, C., Arias-Mayenco, I., Garcia-Flores, P., Garcia-Pergañeda, A., Pascual, A., Ortega-Sáenz, P., and López-Barneo, J. (2015) Oxygen sensing by arterial chemoreceptors depends on mitochondrial complex I signaling, Cell Metab., 22, 825–837, doi: 10.1016/j.cmet.2015.09.004.

104. Tajima, N., Schönherr, K., Niedling, S., Kaatz, M., Kanno, H., Schönherr, R., and Heinemann, S. (2006) Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1alpha and the von Hippel-Lindau protein, J. Physiol., 571, 349–359, doi: 10.1113/jphysiol.2005.096818.

105. Dong, Q., Zhao, N., Xia, C., Du, L., Fu, X., and Du, Y. (2012) Hypoxia induces voltage-gated K+ (Kv) channel expression in pulmonary arterial smooth muscle cells through hypoxia-inducible factor-1 (HIF-1), Bosn. J. Basic Med. Sci., 12, 158–163, doi: 10.17305/bjbms.2012.2463.

106. Shin, D., Lin, H., Zheng, H., Kim, K., Kim, J., Chun, Y., Park, J., Nam, J., Kim, W., Zhang, Y., and Kim, S. (2014) HIF-1α-mediated upregulation of TASK-2 K+ channels augments Ca2+ signaling in mouse B cells under hypoxia, J. Immunol., 193, 4924–4933, doi: 10.4049/jimmunol.1301829.

107. Bautista, L., Castro, M., López-Barneo, J., and Castellano, A. (2009) Hypoxia inducible factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning, Circ. Res., 104, 1364–1372, doi: 10.1161/CIRCRESAHA.108.190645.

108. Takahashi, N., Kuwaki, T., Kiyonaka, S., Numata, T., Kozai, D., Mizuno, Y., Yamomoto, S., Naito, S., Knevels, E., Carmeliet, P., Oqa, T., Kaneko, S., Suqa, S., Nokami, T., Yoshida, J., and Mori, Y. (2011) TRPA1 underlies a sensing mechanism for O2, Nat. Chem. Biol., 7, 701–711, doi: 10.1038/nchembio.640.

109. Nagarajan, Y., Rychkov, G., and Peet, D. (2017) Modulation of TRP channel activity by hydroxylation and its therapeutic potential, Pharmaceuticals (Basel), 10, 1–8, doi: 10.3390/ph10020035.

110. Semenza, G., and Prabhakar, N. (2018) The role of hypoxia-inducible factors in carotid body (patho) physiology, J. Physiol., 596, 2977–2983, doi: 10.1113/JP275696.

111. Macdonald, A., and Vjotosh, A. (1999) Patch-clamp recording of BKCa channels in hyperbaric oxygen, J. Physiol., 518, 111P–112P.

112. Pokorski, M., Takeda, K., and Okada, Y. (2016) Oxygen sensing mechanisms: a physiological penumbra, Adv. Exp. Med. Biol., 952, 1–8, doi: 10.1007/5584_2016_67.

113. Mori, Y., Takahashi, N., Kurokawa, T., and Kiyonaka, S. (2017) TRP channels in oxygen physiology: distinctive functional properties and roles of TRPA1 in O2 sensing, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., 93, 464–482, doi: 10.2183/pjab.93.028.