Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Aug 1;11(8):2163.
doi: 10.3390/biomedicines11082163.

Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway

Dario Troise  1 , Barbara Infante  1 , Silvia Mercuri  1 , Giuseppe Stefano Netti  2 , Elena Ranieri  2 , Loreto Gesualdo  3 , Giovanni Stallone  1 , Paola Pontrelli  3
Affiliations
Review

Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway

Dario Troise et al. Biomedicines. .

Abstract

Hypoxia activates hypoxia-related signaling pathways controlled by hypoxia-inducible factors (HIFs). HIFs represent a quick and effective detection system involved in the cellular response to insufficient oxygen concentration. Activation of HIF signaling pathways is involved in improving the oxygen supply, promoting cell survival through anaerobic ATP generation, and adapting energy metabolism to meet cell demands. Hypoxia can also contribute to the development of the aging process, leading to aging-related degenerative diseases; among these, the aging of the immune system under hypoxic conditions can play a role in many different immune-mediated diseases. Thus, in this review we aim to discuss the role of HIF signaling pathways following cellular hypoxia and their effects on the mechanisms driving immune system senescence.

Keywords: cellular aging; cellular energy; hypoxia-inducible factors; immunosenescence.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of oxygen-dependent regulation of HIF-1α. In normoxic conditions, HIF-1β is expressed constitutively, whereas HIF-1α is hydroxylated in its proline residues by prolyl hydroxylase proteins (PHDs), an oxygen-sensing system that uses oxygen as a substrate. This allows for its degradation, mediated by the von Hippel–Lindau tumor suppressor protein (VHL) via the ubiquitin proteasome pathway. Under low oxygen concentration, the VHL tumor suppressor protein becomes inactivated, which allows HIF-1α and HIF-1β to form a heterodimer in the nucleus, which, by binding to p300/CBP, forms a transcriptional activation complex that binds to the hypoxia response element (HRE) and functions as a transcription factor.
Figure 2
Figure 2
Metabolism of cells exposed to hypoxia and the role of HIF-1α. Under low oxygen conditions the cell metabolism is reprogrammed by HIF-1α through a reduction in cellular oxygen dependence, which allows cell survival and maintains host homeostasis. HIF-1α increases the transcription of several genes that encode for proteins involved in the glycolytic pathway, such as GLUT1 and GLUT3, hexokinases (HK1, 2), phosphoglycerate kinase (PGK1), enolase (ENO1), pyruvate kinase (PKM1), and lactate dehydrogenase A (LDHA), which are useful for the production of ATP in hypoxic cells. A reduction in ATP:AMP ratio in cells exposed to low oxygen concentrations leads to the activation of AMPK through the LKB1-AMPK axis, causing an inhibition of mTOR and therefore protein synthesis. Downregulation in protein synthesis occurs through two major pathways, mTOR (mammalian target of rapamycin) complex and PERK (protein kinase R-like ER kinase), in order to suppress cell expensive energy processes. Hypoxia negatively regulates mTOR-related protein translation, which is no longer able to phosphorylate eIF4E-binding proteins (4E-BPs) and therefore prevents the assimilation of eIF4E into a complex necessary for binding to mRNA cap and initiates translation. Moreover, PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) and inhibits translation initiation to prevent abnormal accumulation of unfolded/misfolded proteins that can cause endoplasmic reticulum stress. To optimize the use of limited energy supplies, the cell activates self-preservation process such as autophagy through HIF-1α-dependent expression of BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein) and HIF-independent mechanism ULK1-AMPK.
Figure 3
Figure 3
Effect of HIFs on immune cell metabolism. The activity of HIFs affects the function and the metabolism of innate and adaptive immune cells in terms of survival, activation, development, and polarization.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aman Y., Schmauck-Medina T., Hansen M., Morimoto R.I., Simon A.K., Bjedov I., Palikaras K., Simonsen A., Johansen T., Tavernarakis N., et al. Autophagy in healthy aging and disease. Nat. Aging. 2021;1:634–650. doi: 10.1038/s43587-021-00098-4. - DOI - PMC - PubMed
    1. Otero-Albiol D., Carnero A. Cellular senescence or stemness: Hypoxia flips the coin. J. Exp. Clin. Cancer Res. 2021;40:243. doi: 10.1186/s13046-021-02035-0. - DOI - PMC - PubMed
    1. Dzhalilova D.S., Makarova O.V. The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging. Biochemistry. 2022;87:995–1014. doi: 10.1134/S0006297922090115. - DOI - PubMed
    1. Palazon A., Goldrath A.W., Nizet V., Johnson R.S. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41:518–528. doi: 10.1016/j.immuni.2014.09.008. - DOI - PMC - PubMed
    1. Wang G.L., Jiang B.H., Rue E.A., Semenza G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA. 1995;92:5510–5514. doi: 10.1073/pnas.92.12.5510. - DOI - PMC - PubMed

Grants and funding

This research received no external funding.

LinkOut - more resources