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Mitochondrial Regulation of Oxygen Sensing

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Membrane Receptors, Channels and Transporters in Pulmonary Circulation

Part of the book series: Advances in Experimental Medicine and Biology ((volume 661))

Abstract

Hypoxia promotes physiological processes such as energy metabolism, angiogenesis, cell proliferation, and cell viability through the transcription factor Hypoxia Inducible Factor (HIF). Hypoxia also diminishes the activity of ATP consuming processes to promote cell survival. The mechanism(s) by which hypoxia activates HIF and diminishes ATP demand are a subject of intensive research. Here we outline the model in which mitochondrial complex III regulate the activity of HIF and diminish ATP utilization processes through the increased production of ROS during hypoxia.

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References

  1. Schroedl C, McClintock DS, Budinger GRS, Chandel NS (2002) Hypoxic but not anoxic stabilization of HIF-1α requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 283:L922-L931

    PubMed  CAS  Google Scholar 

  2. Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551-578

    Article  PubMed  CAS  Google Scholar 

  3. Planès C, Friedlander G, Loiseau A, Amiel C, Clerici C (1996) Inhibition of Na,K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line. Am J Physiol 271:L71-L78

    Google Scholar 

  4. Chandel NS, Budinger GR, Schumacker PT (1996) Molecular oxygen modulates cytochrome c oxidase function. J Biol Chem 271:18672-18677

    Article  PubMed  CAS  Google Scholar 

  5. Aw TY, Jones DP (1982) Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentration. J Biol Chem 257:8997-9004

    PubMed  CAS  Google Scholar 

  6. Forsythe JA, Jiang BH, Iyer NV et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604-4613

    PubMed  CAS  Google Scholar 

  7. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510-5514

    Article  PubMed  CAS  Google Scholar 

  8. Jiang BH, Zheng JZ, Leung SW, Roe R, Semenza GL (1997) Transactivation and inhibitory domains of hypoxia-inducible factor 1α modulation of transcriptional activity by oxygen tension. J Biol Chem 272:19253-19260

    Article  PubMed  CAS  Google Scholar 

  9. Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271-275

    Article  PubMed  CAS  Google Scholar 

  10. Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468-472

    Article  PubMed  CAS  Google Scholar 

  11. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J 20:5197-5206

    Article  PubMed  CAS  Google Scholar 

  12. Ivan M, Kondo K, Yang H et al (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464-468

    Article  PubMed  CAS  Google Scholar 

  13. Epstein AC, Gleadle JM, McNeill LA et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43-54

    Article  PubMed  CAS  Google Scholar 

  14. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick R (2002) FIH-1 is an asparaginyl hydroxylase that regulates the transcriptional activity of hypoxia inducible factor. Genes Dev 16:1466-1471

    Article  PubMed  CAS  Google Scholar 

  15. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295:858-861

    Article  PubMed  CAS  Google Scholar 

  16. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675-2686

    Article  PubMed  CAS  Google Scholar 

  17. Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839-885

    PubMed  CAS  Google Scholar 

  18. Srinivas V, Zhu X, Salceda S, Nakamura R, Caro J (1998) Hypoxia-inducible factor 1α (HIF-1α) is a non-heme iron protein. Implications for oxygen sensing. J Biol Chem 273:18019-18022

    Article  PubMed  CAS  Google Scholar 

  19. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 95:5015-5019

    Article  Google Scholar 

  20. Chandel NS, McClintock DS, Feliciano SE et al (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130-25138

    Article  PubMed  CAS  Google Scholar 

  21. King MP, Attardi G (1988) Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52:811-819

    Article  PubMed  CAS  Google Scholar 

  22. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335-344

    Article  PubMed  CAS  Google Scholar 

  23. Hunte C, Palsdottir H, Trumpower BL (2003) Protonmotive pathways and mechanisms in the cytochrome bc1 complex. FEBS Lett 545:39-46

    Article  PubMed  CAS  Google Scholar 

  24. Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278:5557-5563

    Article  PubMed  CAS  Google Scholar 

  25. Turrens JF, Alexandre A, Lehninger AL (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237:408-414

    Article  PubMed  CAS  Google Scholar 

  26. Boveris A, Cadenas E, Stoppani AO (1976) Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem J 156:435-444

    PubMed  CAS  Google Scholar 

  27. Gupte S, Wu ES, Hoechli L et al (1984) Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components. Proc Natl Acad Sci U S A 81:2606-2610

    Article  PubMed  CAS  Google Scholar 

  28. Kroger A, Klingenberg M (1973) Further evidence for the pool function of ubiquinone as derived from the inhibition of the electron transport by antimycin. Eur J Biochem 39:313-323

    Article  PubMed  CAS  Google Scholar 

  29. Mansfield KD, Guzy RD, Pan Y et al (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1:393-399

    Article  PubMed  CAS  Google Scholar 

  30. Guzy RD, Hoyos B, Robin E et al (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1:401-408

    Article  PubMed  CAS  Google Scholar 

  31. Brunelle JK, Bell EL, Quesada NM et al (2005) Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1:409-414

    Article  PubMed  CAS  Google Scholar 

  32. Rana M, de Coo I, Diaz F, Smeets H, Moraes CT (2000) An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann Neurol 48:774-781

    Article  PubMed  CAS  Google Scholar 

  33. Bell EL, Klimova TA, Eisenbart J et al (2007) The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 177:1029-1036

    Article  PubMed  CAS  Google Scholar 

  34. Hirota K, Semenza GL (2001) Rac1 activity is required for the activation of hypoxia-inducible factor 1. J Biol Chem 276:21166-21172

    Article  PubMed  CAS  Google Scholar 

  35. Turcotte S, Desrosiers RR, Beliveau R (2003) HIF-1α mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. J Cell Sci 116:2247-2260

    Article  PubMed  CAS  Google Scholar 

  36. Chandel NS, Budinger GR, Choe SH, Schumacker PT (1997) Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes. J Biol Chem 272:18808-18816

    Article  PubMed  CAS  Google Scholar 

  37. Milligan LP, McBride BW (1985) Energy costs of ion pumping by animal tissues. J Nutr 115:1374-1382

    PubMed  CAS  Google Scholar 

  38. Kaplan JH (2002) Biochemistry of Na,K-ATPase. Annu Rev Biochem 71:511-535

    Article  PubMed  CAS  Google Scholar 

  39. Carpenter TC, Schomberg S, Nichols C, Stenmark KR, Weil JV (2003) Hypoxia reversibly inhibits epithelial sodium transport but does not inhibit lung ENaC or Na-K-ATPase expression. Am J Physiol Lung Cell Mol Physiol 284:L77-L83

    PubMed  CAS  Google Scholar 

  40. Mairbaurl H, Wodopia R, Eckes S, Schulz S, Bartsch P (1997) Impairment of cation transport in A549 cells and rat alveolar epithelial cells by hypoxia. Am J Physiol Lung Cell Mol Physiol 273:L797-L806

    CAS  Google Scholar 

  41. Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, Sznajder JI (2003) Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-ς. J Clin Invest 111:1057-1064

    PubMed  CAS  Google Scholar 

  42. Chibalin AV, Ogimoto G, Pedemonte CH et al (1999) Dopamine-induced endocytosis of Na+,K+-ATPase is initiated by phosphorylation of Ser-18 in the rat α subunit and is responsible for the decreased activity in epithelial cells. J Biol Chem 274:1920-1927

    Article  PubMed  CAS  Google Scholar 

  43. Konishi H, Tanaka M, Takemura Y et al (1997) Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci U S A 94:11233-11237

    Article  PubMed  CAS  Google Scholar 

  44. Feschenko MS, Sweadner KJ (1997) Phosphorylation of Na,K-ATPase by protein kinase C at Ser18 occurs in intact cells but does not result in direct inhibition of ATP hydrolysis. J Biol Chem 272:17726-17733

    Article  PubMed  CAS  Google Scholar 

  45. Bruick RK (2003) Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev 17:2614-2623

    Article  PubMed  CAS  Google Scholar 

  46. Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J (2003) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 278:30772-30780

    Article  PubMed  Google Scholar 

  47. Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271:C1172-C1180

    PubMed  CAS  Google Scholar 

  48. Gleadle JM, Ebert BL, Ratcliffe PJ (1995) Diphenylene iodonium inhibits the induction of erythropoietin and other mammalian genes by hypoxia. Implications for the mechanism of oxygen sensing. Eur J Biochem 234:92-99

    Article  PubMed  CAS  Google Scholar 

  49. Killilea DW, Hester R, Balczon R, Babal P, Gillespie MN (2000) Free radical production in hypoxic pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 279:L408-L412

    PubMed  CAS  Google Scholar 

  50. Wood JG, Johnson JS, Mattioli LF, Gonzalez NC (1999) Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation. J Appl Physiol 87:1734-1740

    PubMed  CAS  Google Scholar 

  51. Fandrey J, Frede S, Jelkmann W (1994) Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem J 303:507-510

    PubMed  CAS  Google Scholar 

  52. Tarpey MM, Fridovich I (2001) Methods of detection of vascular reactive species: nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite. Circ Res 89:224-236

    Article  PubMed  CAS  Google Scholar 

  53. Dirmeier R, O’Brien KM, Engle M, Dodd A, Spears E, Poyton RO (2002) Exposure of yeast cells to anoxia induces transient oxidative stress. Implications for the induction of hypoxic genes. J Biol Chem 277:34773-34784

    Article  PubMed  CAS  Google Scholar 

  54. Grishko V, Solomon M, Breit JF et al (2001) Hypoxia promotes oxidative base modifications in the pulmonary artery endothelial cell VEGF gene. FASEB J 15:1267-1269

    PubMed  CAS  Google Scholar 

  55. Liu Q, Kuppusamy P, Sham JSK, Shimoda LA, Zweier JL, Sylvester JT (2001) Increased production of reactive oxygen species (ROS) by pulmonary arterial smooth muscle is required for hypoxic pulmonary vasoconstriction (HPV). Am J Respir Crit Care Med 163:A395

    Google Scholar 

  56. Agani FH, Pichiule P, Chavez JC, LaManna JC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 275:35863-35867

    Article  PubMed  CAS  Google Scholar 

  57. Enomoto N, Koshikawa N, Gassmann M, Hayashi J, Takenaga K (2002) Hypoxic induction of hypoxia-inducible factor-1α and oxygen-regulated gene expression in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun 297:346-352

    Article  PubMed  CAS  Google Scholar 

  58. Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, Caro J (2001) Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J Biol Chem 276:21995-21998

    Article  PubMed  CAS  Google Scholar 

  59. Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ (2001) Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 98:296-302

    Article  PubMed  CAS  Google Scholar 

  60. Miranda S, Foncea R, Guerrero J, Leighton F (1999) Oxidative stress and upregulation of mitochondrial biogenesis genes in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun 258:44-49

    Article  PubMed  CAS  Google Scholar 

  61. Paddenberg R, Ishaq B, Goldenberg A et al (2003) Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol 284:L710-L719

    PubMed  CAS  Google Scholar 

  62. Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α.Science 302:1975-1978

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH grant GM60472-09.

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Correspondence to Navdeep S. Chandel .

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Chandel, N.S. (2010). Mitochondrial Regulation of Oxygen Sensing. In: Yuan, JJ., Ward, J. (eds) Membrane Receptors, Channels and Transporters in Pulmonary Circulation. Advances in Experimental Medicine and Biology, vol 661. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-500-2_22

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