Hypoxia-inducible Factors—Their Regulation and Function in Neural Tissue

Abstract

Hypoxia-inducible factors (HIF) are key transcription factors that alter gene expression in hypoxia, and play a central role in ensuring an adaptive response to low oxygen levels in the brain. This review provides information on the functional role of HIF in adaptive tissue responses, specifically in response to metabolic shifts, in angiogenesis, apoptosis and others, which plays an important role in cell survival under hypoxic conditions. We describe the molecular structure of the main HIF subunits, changes in their expression and decay at normal oxygen levels, as well as in acute and chronic hypoxia, and the factors regulating these changes. Special attention is paid to the role of microRNAs in regulating HIF changes, as well as the interaction of HIF subunits with mitochondrial factors. The role of HIF in neuroprotection and neuroglial adaptive changes is described in detail. The importance of further study of HIF’s physiological role is noted, to obtain new information about the pathogenesis of hypoxic brain injury, including its early stages, which determines the risk of later neurological disease.

This is a preview of subscription content, access via your institution.

REFERENCES

  1. 1

    Semenza, G.L., Hypoxia-inducible factors in physiology and medicine, Cell, 2012, vol. 148, p. 399.

    CAS  Article  Google Scholar 

  2. 2

    Luk’yanova, L.D, Signal’nye mekhanizmy gipoksii (Signaling Mechanisms of Hypoxia), Moscow: Ross. Akad. Nauk, 2019.

  3. 3

    Baranich, T., Voronkova, A., Kirova, Yu., et al., Role of hypoxia-inducible factor 1-alpha in pathogenesis of muscular dystrophies in children, Proc. 9th World Cong. on Targeting Mitochondria, Abstracts of Papers, Berlin: World Mitochondria Soc., 2018, p. 68.

  4. 4

    Koh, M.Y. and Powis, G. Passing the baton: the HIF switch, Trends Biochem. Sci., 2012, vol. 37, p. 364.

    CAS  Article  Google Scholar 

  5. 5

    Semenza, G.L., Regulation of gene transcription by hypoxia-inducible factor 1, in Encyclopedia of Biological Chemistry, London, 2013, vol. 2, p. 67.

  6. 6

    Palazon, A., Goldrath, A.W., Nizet, V., and Johnson, R.S., HIF transcription factors, inflammation, and immunity, Immunity, 2014, vol. 41, p. 518.

    CAS  Article  Google Scholar 

  7. 7

    Kenneth, N.S. and Rocha, S., Regulation of gene expression by hypoxia, Biochem. J., 2008, vol. 414, p. 19.

    CAS  Article  Google Scholar 

  8. 8

    Correia, S.C. and Moreira, P.I., Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration? J. Neurochem., 2010, vol. 112, p. 1.

    CAS  Article  Google Scholar 

  9. 9

    Wu, D., Potluri, N., Lu, J., et al., Structural integration in hypoxia-inducible factors, Nature, 2015, vol. 524, p. 303.

    CAS  Article  Google Scholar 

  10. 10

    Huang, L.E., Gu, J., Schau, G., and Bunn, H.F., Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway, Proc. Natl. Acad. Sci. U.S.A., 1998, vol. 95, no. 14, p. 7987.

    CAS  Article  Google Scholar 

  11. 11

    Loboda, A., Jozkowicz, A., and Dulak, J., HIF-1 versus HIF-2—Is one more important than the other? Vasc. Pharmacol., 2012, vol. 56, p. 245.

    CAS  Article  Google Scholar 

  12. 12

    Smythies, J.A., Sun, M., Masso, N., et al., Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin, EMBO Rep., 2019, vol. 20, p. 46401.

    Article  Google Scholar 

  13. 13

    Gu, Y.Z., Moran, S.M., Hogenesch, J.B., et al., Molecular characterization and chromosomal localization of a third α-class hypoxia inducible factor subunit, HIF3α, Gene Expression, 1998, vol. 7, p. 205.

    CAS  PubMed  Google Scholar 

  14. 14

    Zhao, J., Du, F., Shen, G., et al., The role of hypoxia- inducible factor-2 in digestive system cancers, Cell Death Dis., 2015, vol. 6, p. 1600.

    Article  Google Scholar 

  15. 15

    Keith, B., Johnson, R.S., and Simon, M.C., HIF1α and HIF2α: sibling rivalry in hypoxic tumor growth and progression, Nat. Rev. Cancer, 2012, vol. 12, p. 9

    CAS  Article  Google Scholar 

  16. 16

    Mahon, P.C., FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity, Genes Dev., 2001, vol. 15, p. 2675.

    CAS  Article  Google Scholar 

  17. 17

    Koivunen, P., Hirsilä, M., Günzler, V., et al., Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases, J. Biol. Chem., 2004, vol. 279, p. 9899.

    CAS  Article  Google Scholar 

  18. 18

    Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., et al., Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype, Cancer Cell, 2006, vol. 10, p. 413.

    CAS  Article  Google Scholar 

  19. 19

    Holmquist, L., Jogi, A., and Påhlman, S., Phenotypic persistence after reoxygenation of hypoxic neuroblastoma cells, Int. J. Cancer, 2005, vol. 116, p. 218.

    CAS  Article  Google Scholar 

  20. 20

    Koh, M.Y., Lemos, R., Liu, X., and Powis, G., The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion, Cancer Res., 2011, vol. 71, p. 4015.

    CAS  Article  Google Scholar 

  21. 21

    Lin, Q., Cong, X., and Yun, Z., Differential hypoxic regulation of hypoxia-inducible factors 1α and 2α, Mol. Cancer Res., 2011, vol. 9, p. 757.

    CAS  Article  Google Scholar 

  22. 22

    Luo, W., Zhong, J., Chang, R., et al., Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α, J. Biol. Chem., 2010, vol. 285, p. 3651.

    CAS  Article  Google Scholar 

  23. 23

    Bento, C.F., Fernandes, R., Ramalho, J., et al., The chaperone- dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal, PLoS One, 2010, vol. 5, p. 15062.

    Article  Google Scholar 

  24. 24

    Koh, M.Y., Darnay, B.G., and Powis, G., Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation, Mol. Cell Biol., 2008, vol. 28, p. 7081.

    CAS  Article  Google Scholar 

  25. 25

    Uchida, T., Rossignol, F., Matthay, M.A., et al., Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1α and HIF-2α expression in lung epithelial cells: implication of natural antisense HIF-1α, J. Biol. Chem., 2004, vol. 279, p. 14871.

    CAS  Article  Google Scholar 

  26. 26

    Cavadas, M.A.S., Mesnieres, M., Crifo, B., et al., REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia, Sci. Rep., 2015, vol. 5, p. 17851.

    CAS  Article  Google Scholar 

  27. 27

    Serocki, M., Bartoszewska, S, Janaszak-Jasiecka, A., et al., MiRNAs regulate the HIF switch during hypoxia: a novel therapeutic target, Angiogenesis, 2018, vol. 21, p. 183–202.

    CAS  Article  Google Scholar 

  28. 28

    Braicu, C., Catana, C., Calin, G.A., and Berindan-Neagoe, I., NCRNA combined therapy as future treatment option for cancer, Curr. Pharm. Des., 2014, vol. 20, p. 6565.

    CAS  Article  Google Scholar 

  29. 29

    Bica-Pop, C., Cojocneanu-Petric, R., Magdo, L., et al., Overview upon miR-21 in lung cancer: focus on NSCLC, Cell. Mol. Life Sci., 2018, vol. 75, p. 3539.

    CAS  Article  Google Scholar 

  30. 30

    Redis, R.S, Berindan-Neagoe, I., Pop, V.I., and Calin, G.A., Non-coding RNAs as theranostics in human cancers, J. Cell. Biochem., 2012, vol. 113, p. 1451.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    O’Brien, J., Hayder, H., Zayed, Y., and Peng, C., Overview of microRNA biogenesis, mechanisms of actions, and circulation, Front. Endocrinol., 2018, vol. 9, p. 402.

    Article  Google Scholar 

  32. 32

    Janaszak-Jasiecka, A., Bartoszewska, S., Kochan, K., et al., miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells, Sci. Rep., 2016, vol. 6, p. 22775.

    CAS  Article  Google Scholar 

  33. 33

    Stowers, R.S., Megeath, L.J., Gorska-Andrzejak, J., et al., Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein, Neuron, 2002, vol. 36, p. 1063

    CAS  Article  Google Scholar 

  34. 34

    Brunelle, J.K., Bell, E.L., Quesada, N.M., et al., Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation, Cell Metab., 2005, vol. 1, p. 409.

    CAS  Article  Google Scholar 

  35. 35

    Guzy, R.D., Hoyos, B., Robin, E., et al., Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab., 2005, vol. 1, p. 401.

    CAS  Article  Google Scholar 

  36. 36

    Bell, E.L., Klimova, T.A., Eisenbart, J., et al., The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production, J. Cell Biol., 2007, vol. 177, p. 1029.

    CAS  Article  Google Scholar 

  37. 37

    Briston, T., Yang, J., and Ashcroft, M., HIF-1α localization with mitochondria: a new role for an old favorite? Cell Cycle, 2011, vol. 10, p. 4170.

    CAS  Article  Google Scholar 

  38. 38

    Mylonis, I., Kourti, M., Samiotaki, M., et al., Mor-talin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia, J. Cell Sci., 2017, vol. 130, no. 2, p. 466.

    CAS  Article  Google Scholar 

  39. 39

    Hirayama, Y. and Koizumi, S., Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning, Glia, 2017, vol. 65, p. 523

    Article  Google Scholar 

  40. 40

    Hirayama, Y., Ikeda-Matsuo, Y., and Notomi, S., Astrocyte-mediated ischemic tolerance, J. Neurosci., 2015, vol. 35, p. 3794.

    CAS  Article  Google Scholar 

  41. 41

    Ruscher, K., Freyer, D., Karsch, M., et al., Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model, J. Neurosci., 2002, vol. 22, p. 10291.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to T. I. Baranich.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Baranich, T.I., Voronkova, A.S., Anufriev, P.L. et al. Hypoxia-inducible Factors—Their Regulation and Function in Neural Tissue. Hum Physiol 46, 895–899 (2020). https://doi.org/10.1134/S0362119720080022

Download citation

Keywords:

  • hypoxia
  • HIF
  • mitochondria
  • neuroprotection
  • astrocyte
  • nervous tissue