Ulyanovsk Medico-biological Journal

PHYSIOLOGY

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DOI 10.34014/2227-1848-2019-3-52-62

 

INTERACTION OF OXYGEN-SENSING MECHANISMS IN CELLS

 

A.N. Vetosh

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia;

Lesgaft National State University of Physical Education, Sport and Health, St. Petersburg, Russia;

North-Western State Medical University named after I.I. Mechnikov, St. Petersburg, Russia

e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Reactions of the human body to chronic, acute or interval hypoxic hypoxia are different and may be triggered by certain intracellular molecular mechanisms. The authors analyzed PubMed database using the keywords “intracellular oxygen sensing” to verify the assumption. In 1977–2019, almost 1000 papers were published on the issue including more than 50 reviews. For their analysis, the authors chose articles on molecular oxygen sensing Metazoan tissue cells, mainly animals.

Cell responses to chronic hypoxia are determined by HIF-pool localized in the cytoplasm. Oxygen-sensing to acute hypoxia in cells is preconditioned by molecular mechanisms involving potassium channels of plasma cell membranes and associated juxtamembrane complexes. Molecular intracellular reactions to interval hypoxia are triggered by the prooxidant process activation in the mitochondria of cells. This review discusses the interactional characteristics of the three mechanisms of oxygen-sensing cells.

Keywords: oxygen, HIF, potassium channels of plasma membranes, mitochondria, ROS.

 

References

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  2. Kolchinskaya A.Z., Tsyganova T.N., Ostapenko L.A. Normobaricheskaya interval'naya gipoksicheskaya trenirovka v meditsine i sporte [Normobaric interval hypoxic training in medicine and sports]. Moscow: Meditsina; 2003. 406 (in Russian).

  3. Lei Xi, Serebrovskaya T.V., eds. Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc; 2009. 615.

  4. Semenza G. Oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2010; 2 (3): 336–361.

  5. Lin F., Suggs S., Lin C., Browne J., Smalling R., Egrie J., Chen K., Fox G., Martin F., Stabinsky Z. Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. USA. 1985; 82 (22): 7580–7584.

  6. Semenza G., Wang G. 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. 1992; 12 (12): 5447–5454.

  7. Bishop T., Ratcliffe P. Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives. Hypoxia (Auckl.). 2014; 2: 197–213.

  8. Masson N., Willam C., Maxwell P., Pugh C., Ratcliffe P. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001; 20 (18): 5197–5206.

  9. Anokhina E.B., Buravkova L.B. Mekhanizmy regulyatsii transkriptsionnogo faktora pri gipoksii (obzor) [Transcription factor regulation mechanisms under hypoxia (review)]. Biokhimiya. 2010; 75 (2): 185–195 (in Russian).

  10. Samanta D., Prabhakar N., Semenza G. Systems biology of oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2017; 9 (4): 1–15.

  11. Semenza G. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol. Aspects Med. 2016; 47–48: 15–23.

  12. Prabhakar N., Semenza G. Regulation of carotid body oxygen sensing by hypoxia-inducible factors. Pflugers Arch. 2016; 468 (1): 71–75.

  13. Hirsilä M., Koivunen P., Günzler V., Kivirikko K., Myllyharju J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 2003; 278 (33): 30772–30780. 

  14. Maltepe E., Schmidt J., Baunoch D., Bradfield C., Simon M. Abnormal Angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature. 1997; 386 (6623): 403–407.

  15. Townley-Tilson W., Pi X., Xie L. The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease. Oxid. Med. Cell Longey. 2015; 2015: 676893.

  16. Bell E., Chandel N. Mitochondrial Oxygen sensing: regulation of Hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem. 2007; 43: 17–27.

  17. Coleman M., Ratcliffe P.J. Oxygen sensing and Hypoxia-induced responses. Essays in Biochemistry. 2007; 43: 1–16.

  18. Pogodina M.V., Buravkova L.B. Osobennosti ekspressii HIF-1A v mul'tipotentnykh mezenkhimnykh stromal'nykh kletkakh pri gipoksii (obzor) [Expression of HIF-1α in multipotent mesenchymal stromal cells under hypoxia (review)]. Byulleten' eksperimental'noy biologii i meditsiny. 2015; 159: 333–335 (in Russian).

  19. Waypa G., Smith K., Schumacher P. O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol. Aspects Med. 2016; 47–48: 76–89.

  20. Lopez-Barneo J., Lopez-Lopez J., Urena J., Gonzalez C. Chemotransduction in the carotid body:

    K+ current modulated by PO2 in type I chemoreceptor cells. Science. 1988; 241 (4865): 580–582.

  21. Haddad G., Jiang C. O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels. Ann. Rev. Physiol. 1997; 59: 23–42.

  22. Prabhakar N., Peers C. Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology (Bethesda). 2014; 29 (1): 49–57.

  23. Hoshi T., Lahiri S. Cell biology. Oxygen sensing: it's a gas! Cell Biol. 2004; 306 (5704): 2050–2051.

  24. Kemp P., Peers C. Oxygen sensing by ion channels. Essays Biochem. 2007; 43: 77–90.

  25. Peers C., Wyatt C., Evans A. Mechanisms for acute oxygen sensing in the carotid body. Respiratory Physiology & Neurobiology. 2010; 174 (3): 292–298.

  26. Williams S., Wootton P., Mason H., Bould J., Iles D., Riccardi D., Peers C., Kemp P. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science. 2004; 306 (5704): 2093–2097.

  27. Hou S., Heinemann S., Hoshi T. Modulation of BKCa channel gating by endogenous signaling molecules. Physiology (Bethesda). 2009; 24: 26–35.

  28. Peng Y., Nanduri J., Raghuraman G., Souvannakitti D., Gadalla M., Kumar G., Snyder S., Prabhakar N. H2S mediates O2 sensing in the carotid body. Proc. Natl. Acad. Sci. USA. 2010; 107 (23): 10719–10724.

  29. Li Q., Sun B., Wang X., Jin Z., Zhou Y., Dong L., Jiang L., Rong W. A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-activated potassium channels. Antioxid. Redox Signal. 2010; 12 (10): 1179–1189.

  30. Li Y., Zheng H., Ding Y., Schultz H. Expression of neuronal nitric oxide synthase in rabbit carotid body glomus cells regulates large-conductance Ca2+-activated potassium currents. J. Neurophysiol. 2010; 103 (6): 3027–3033.

  31. Lukyanova L.D., Dudchenko A.V., Germanova E.L. Mitochondrial signaling in formation of body resistance to hypoxia. In: Lei Xi, Serebrovskaya T.V. (Eds.). Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 391–417.

  32. Sazontova T.G., Arkhipenko Y.V. Intermittent hypoxia in resistance of cardiac membrane structures: role of reactive oxygen species and redox signaling. In: Lei Xi, Serebrovskaya T.V. (Eds.). Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 113–150.

  33. Manukhina E.B., Vanin A.F., Malyshev I.Yu. Intermittent hypoxia-Induced cardio- and vasoprotection: role of NO stores. In: Lei Xi, Serebrovskaya T.V. (eds.). Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 79–112.

  34. Mansfield K., Guzy R., Pan Y., Young R., Cash T., Schumacker P., Simon M. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 2005; 1 (6): 393–399.

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

  36. Finkel T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 2012; 287 (7): 4434–4440.

  37. Brand M. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 2016; 100: 14–31.

  38. Vetosh A.N. Biologicheskoe deystvie azota [Biological effects of nitrogen]. St. Petersburg; 2003. 231 (in Russian).

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  40. Zhong N., Zhang Y., Fang Q.Z., Zhou Z.N. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol. Sin. 2000; 21 (5): 467–472.

  41. Murphy M., Holmgren A., Larsson N., Halliwell B., Chang C., Kalyanaraman B., Rhee S., Thornalley P., Partridge L., Gem, D., Nyström T., Belousov V., Schumacker P., Winterbourn C. Unraveling the biological roles of reactive oxygen Species. Cell Metab. 2011; 13 (4): 361–366.

  42. Semenza G. Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148 (3): 399–408.

  43. Ivan M., Kaelin Jr. The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks. Mol. Cell. 2017; 66 (6): 772–779.

  44. Kim J., Tchernyshyov I., Semenza G., Dang C. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; (3): 177–185.

  45. McElroy G., Chandel N. Mitochondria control acute and chronic responses to hypoxia. Exp. Cell Res. 2017; 356 (2): 217–222.

  46. Fernández-Agüera M., Gao L., González-Rodríguez P., Pintado C., Arias-Mayenco I., García-Flores P., García-Pergañeda A., Pascual A., Ortega-Sáenz P., López-Barneo J. Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling. Cell Metab. 2015; 22 (5): 825–837.

  47. Ward J. Oxygen sensors in context. Biochimica et Biophysica Acta. 2008; 1777 (1): 1–14.

  48. Tajima N., Schönherr K., Niedling S., Kaatz M., Kanno H., Schönherr R., Heinemann S. Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1-alpha and the von Hippel-Lindau protein. J. Physiol. 2006; 571 (Pt 2): 349–359.

  49. Don Q., Zhao N., Xia C., Fu X., Du Y. 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. 2012; 12 (3): 158–163.

  50. Shin D., Lin H., Zheng H., Kim K., Kim J., Chun Y., Park J., Nam J., Kim W., Zhang Y., Kim S. HIF-1α-mediated upregulation of TASK-2 K+ channels augments Ca²+ signaling in mouse B cells under hypoxia. J. Immunol. 2014; 193 (10): 4924–4933.

  51. Bautista L., Castro M., López-Barneo J., Castellano A. Hypoxia inducible Factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning. Circ. Res. 2009; 10 (12): 1364–1372.

 

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УДК 612.26; 612.22

DOI 10.34014/2227-1848-2019-3-52-62

 

ВЗАИМОДЕЙСТВИЕ КИСЛОРОДЧУВСТВИТЕЛЬНЫХ МЕХАНИЗМОВ В КЛЕТКЕ

 

А.Н. Ветош

ФГБУН Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН, г. Санкт-Петербург, Россия;

ФГБОУ ВО «Национальный государственный университет физической культуры, спорта и здоровья им. П.Ф. Лесгафта», г. Санкт-Петербург, Россия;

ФГБОУ ВО «Северо-Западный государственный медицинский университет им. И.И. Мечникова», г. Санкт-Петербург, Россия

e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Реакции организма человека на хроническую, острую или интервальную гипоксическую гипоксию различны и, возможно, запускаются отдельными внутриклеточными молекулярными механизмами. Для проверки этого предположения был проведен анализ литературных данных базы PubMed по ключевым словам «intracellular oxygen sensing». За период 1977–2019 гг. по данному вопросу было опубликовано почти 1000 работ, среди которых более 50 обзоров. Для анализа выбирались публикации, касающиеся молекулярной чувствительности к кислороду клеток тахитрофных тканей Metazoa, по преимуществу животных.

Реакции клеток на хроническую гипоксию определяются HIF-пулом, локализованным в их цитоплазме. Кислородная чувствительность клеток к острой гипоксии обусловлена молекулярными механизмами при участии калиевых каналов плазматических клеточных мембран и ассоциированных с ними околомембранных комплексов. Молекулярные внутриклеточные реакции на интервальную гипоксию запускаются путем активизации прооксидантных процессов в митохондриях клеток. В данном обзоре обсуждаются особенности взаимодействия этих трех механизмов кислородной чувствительности клеток.

Ключевые слова: кислород, HIF, калиевые каналы плазматических мембран, митохондрии, АФК.

 

Литература

  1. Малкин И.Б., Гиппенрейтер Е.Б. Острая и хроническая гипоксия. Т. 35. Москва: Наука; 1977. 319.

  2. Колчинская А.З., Цыганова Т.Н., Остапенко Л.А. Нормобарическая интервальная гипоксическая тренировка в медицине и спорте. Москва: Медицина; 2003. 406.

  3. Lei Xi, Serebrovskaya T.V., eds. Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc; 2009. 615.

  4. Semenza G. Oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2010; 2 (3): 336–361.

  5. Lin F., Suggs S., Lin C., Browne J., Smalling R., Egrie J., Chen K., Fox G., Martin F., Stabinsky Z. Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. USA. 1985; 82 (22): 7580–7584.

  6. Semenza G., Wang G. 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. 1992; 12 (12): 5447–5454.

  7. Bishop T., Ratcliffe P. Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives. Hypoxia (Auckl.). 2014; 2: 197–213.

  8. Masson N., Willam C., Maxwell P., Pugh C., Ratcliffe P. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001; 20 (18): 5197–5206.

  9. Анохина Е.Б., Буравкова Л.Б. Механизмы регуляции транскрипционного фактора при гипоксии (обзор). Биохимия. 2010; 75 (2): 185–195.

  10. Samanta D., Prabhakar N., Semenza G. Systems biology of oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2017; 9 (4): 1–15.

  11. Semenza G. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol. Aspects Med. 2016; 47–48: 15–23.

  12. Prabhakar N., Semenza G. Regulation of carotid body oxygen sensing by hypoxia-inducible factors. Pflugers Arch. 2016; 468 (1): 71–75.

  13. Hirsilä M., Koivunen P., Günzler V., Kivirikko K., Myllyharju J. Characterization of the human prolyl

    4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 2003; 278 (33): 30772–30780. 

  14. Maltepe E., Schmidt J., Baunoch D., Bradfield C., Simon M. Abnormal Angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature. 1997; 386 (6623): 403–407.

  15. Townley-Tilson W., Pi X., Xie L. The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease. Oxid. Med. Cell Longey. 2015; 2015: 676893.

  16. Bell E., Chandel N. Mitochondrial Oxygen sensing: regulation of Hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem. 2007; 43: 17–27.

  17. Coleman M., Ratcliffe P.J. Oxygen sensing and Hypoxia-induced responses. Essays in Biochemistry. 2007; 43: 1–16.

  18. Погодина М.В., Буравкова Л.Б. Особенности экспрессии HIF-1A в мультипотентных мезенхимных стромальных клетках при гипоксии (обзор). Бюллетень экспериментальной биологии и медицины. 2015; 159: 333–335.

  19. Waypa G., Smith K., Schumacher P. O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol. Aspects Med. 2016; 47–48: 76–89.

  20. Lopez-Barneo J., Lopez-Lopez J., Urena J., Gonzalez C. Chemotransduction in the carotid body: K+ current modulated by PO2 in type I chemoreceptor cells. Science. 1988; 241 (4865): 580–582.

  21. Haddad G., Jiang C. O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels. Ann. Rev. Physiol. 1997; 59: 23–42.

  22. Prabhakar N., Peers C. Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology (Bethesda). 2014; 29 (1): 49–57.

  23. Hoshi T., Lahiri S. Cell biology. Oxygen sensing: it's a gas! Cell Biol. 2004; 306 (5704): 2050–2051.

  24. Kemp P., Peers C. Oxygen sensing by ion channels. Essays Biochem. 2007; 43: 77–90.

  25. Peers C., Wyatt C., Evans A. Mechanisms for acute oxygen sensing in the carotid body. Respiratory Physiology & Neurobiology. 2010; 174 (3): 292–298.

  26. Williams S., Wootton P., Mason H., Bould J., Iles D., Riccardi D., Peers C., Kemp P. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science. 2004; 306 (5704): 2093–2097.

  27. Hou S., Heinemann S., Hoshi T. Modulation of BKCa channel gating by endogenous signaling molecules. Physiology (Bethesda). 2009; 24: 26–35.

  28. Peng Y., Nanduri J., Raghuraman G., Souvannakitti D., Gadalla M., Kumar G., Snyder S., Prabhakar N. H2S mediates O2 sensing in the carotid body. Proc. Natl. Acad. Sci. USA. 2010; 107 (23): 10719–10724.

  29. Li Q., Sun B., Wang X., Jin Z., Zhou Y., Dong L., Jiang L., Rong W. A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-activated potassium channels. Antioxid. Redox Signal. 2010; 12 (10): 1179–1189.

  30. Li Y., Zheng H., Ding Y., Schultz H. Expression of neuronal nitric oxide synthase in rabbit carotid body glomus cells regulates large-conductance Ca2+-activated potassium currents. J. Neurophysiol. 2010; 103 (6): 3027–3033.

  31. Lukyanova L.D., Dudchenko A.V., Germanova E.L. Mitochondrial signaling in formation of body resistance to hypoxia. In: Lei Xi, Serebrovskaya T.V. (Eds.), Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 391–417.

  32. Sazontova T.G., Arkhipenko Y.V. Intermittent hypoxia in resistance of cardiac membrane structures: role of reactive oxygen species and redox signaling. In: Lei Xi, Serebrovskaya T.V. (Eds.), Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 113–150.

  33. Manukhina E.B., Vanin A.F., Malyshev I.Yu. Intermittent hypoxia-Induced cardio- and vasoprotection: role of NO stores. In: Lei Xi, Serebrovskaya T.V. (еds.), Intermittent Hypoxia. N.Y.: Nova Science Publishers, Inc.; 2009: 79–112.

  34. Mansfield K., Guzy R., Pan Y., Young R., Cash T., Schumacker P., Simon M. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 2005; 1 (6): 393–399.

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

  36. Finkel T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 2012; 287 (7): 4434–4440.

  37. Brand M. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 2016; 100: 14–31.

  38. Ветош А.Н. Биологическое действие азота. Санкт-Петербург; 2003. 231.

  39. Алексеева О.С., Ветош А.Н., Коржевский Д.Э., Косткин В.Б. Влияние кверцитина на развитие азотного наркоза и накопление белков теплового шока в клетках коры головного мозга крыс. Доклады академии наук. 2010; 430 (3): 421–423.

  40. Zhong N., Zhang Y., Fang Q.Z., Zhou Z.N. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol. Sin. 2000; 21 (5): 467–472.

  41. Murphy M., Holmgren A., Larsson N., Halliwell B., Chang C., Kalyanaraman B., Rhee S., Thornalley P., Partridge L., Gem, D., Nyström T., Belousov V., Schumacker P., Winterbourn C. Unraveling the biological roles of reactive oxygen Species. Cell Metab. 2011; 13 (4): 361–366.

  42. Semenza G. Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148 (3): 399–408.

  43. Ivan M., Kaelin Jr. The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks. Mol. Cell. 2017; 66 (6): 772–779.

  44. Kim J., Tchernyshyov I., Semenza G., Dang C. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; (3): 177–185.

  45. McElroy G., Chandel N. Mitochondria control acute and chronic responses to hypoxia. Exp. Cell Res. 2017; 356 (2): 217–222.

  46. Fernández-Agüera M., Gao L., González-Rodríguez P., Pintado C., Arias-Mayenco I., García-Flores P., García-Pergañeda A., Pascual A., Ortega-Sáenz P., López-Barneo J. Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling. Cell Metab. 2015; 22 (5): 825–837.

  47. Ward J. Oxygen sensors in context. Biochimica et Biophysica Acta. 2008; 1777 (1): 1–14.

  48. Tajima N., Schönherr K., Niedling S., Kaatz M., Kanno H., Schönherr R., Heinemann S. Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1-alpha and the von Hippel-Lindau protein. J. Physiol. 2006; 571 (Pt 2): 349–359.

  49. Don Q., Zhao N., Xia C., Fu X., Du Y. 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. 2012; 12 (3): 158–163.

  50. Shin D., Lin H., Zheng H., Kim K., Kim J., Chun Y., Park J., Nam J., Kim W., Zhang Y., Kim S. HIF-1α-mediated upregulation of TASK-2 K+ channels augments Ca²+ signaling in mouse B cells under hypoxia. J. Immunol. 2014; 193 (10): 4924–4933.

  51. Bautista L., Castro M., López-Barneo J., Castellano A. Hypoxia inducible Factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning. Circ. Res. 2009; 10 (12): 1364–1372.