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Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

Nature Reviews Molecular Cell Biology volume 21, pages 268–283 (2020)Cite this article

Abstract

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.

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Fig. 1: Transcription regulation induced by hypoxia.
Fig. 2: Hypoxic adaptations in proteostasis.
Fig. 3: Impact of hypoxia on mitochondrial function.
Fig. 4: Overview of sugar and lipid metabolic pathways affected by oxygen availability.
Fig. 5: Regulation of nutrient acquisition and use under hypoxia.

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Acknowledgements

N.S.C. acknowledges support by R35CA197532 from the National Institutes of Health (NIH). M.S.C. is supported by P01CA104838 and R35CA220483 from the NIH. P.L. is supported by T32AR53461-10 and F32CA217185-02 from the NIH. The authors have no financial interests to disclose. The authors apologize to those authors whose research could not be directly cited due to space limitations.

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Pearl Lee & M. Celeste Simon

  2. Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Navdeep S. Chandel

  3. Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Navdeep S. Chandel

  4. Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    M. Celeste Simon

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  1. Pearl Lee
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The authors contributed equally to all aspects of the article.

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Correspondence to Pearl Lee, Navdeep S. Chandel or M. Celeste Simon.

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Supplementary information

Glossary

Dioxygenases

A group of enzymes that reduce molecular oxygen by incorporating both oxygen atoms into their substrates.

von Hippel–Lindau (VHL) tumour suppressor protein

(pVHL). A protein named after the physicians von Hippel and Lindau, who characterized patients with highly vascular neoplasia of the kidney, eye and central nervous system who carried mutations in the VHL gene. pVHL is required for the ubiquitylation of hypoxia inducible factor-α and its degradation.

Carotid body

A cluster of peripheral chemoreceptor cells (glomus type I and glomus type II), which sense oxygen, carbon dioxide and pH levels of blood.

Erythropoietin

A glycoprotein cytokine secreted by the kidney in response to hypoxia to stimulate erythropoiesis.

Elongin BC–CUL2

Additional complexes that interact with von Hippel–Lindau (VHL) tumour suppressor protein (pVHL). The Elongin BC complex acts as an adaptor connecting Cullin (Cul) proteins.

Michaelis constant

(Km). The substrate concentration at half of the maximum reaction velocity.

Acidosis

The process or condition where there is increased acidity in the blood and other body tissues.

Cap-dependent protein synthesis

Eukaryotic mRNAs contain a modified guanosine (the cap) at their 5′ ends. Cap-dependent translation requires the binding of an initiation factor, eukaryotic translation initiation factor 4E (eIF4E), to the cap structure.

PERK

(Protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase). A sensor of ER stress and stress-induced protein misfolding.

mTOR

(Mechanistic target of rapamycin). A protein kinase that regulates protein synthesis and cell growth in response to growth factors, nutrients, energy levels and stress.

Eukaryotic initiation factor 2

(eIF2). A complex comprising α, β and γ components that integrates a diverse array of stress-related signals to regulate both global and specific mRNA translation.

ER stress

A condition when the capacity of the endoplasmic reticulum (ER) to fold proteins becomes saturated due to impaired protein glycosylation or disulfide bond formation, or by overexpression of or mutations in proteins entering the secretory pathway.

eIF4F

The cap-binding eukaryotic translation initiation factor 4F (eIF4F) complex consists of three subunits, eIF4A, eIF4E and eIF4G. eIF4G strongly associates with eIF4E, the protein that directly binds the mRNA cap.

ATF4

(Activating transcription factor 4). A cAMP-response element binding protein that belongs to the cAMP response element-binding protein 2 (CREB2) family of transcription factors.

Integrated stress response

An adaptive pathway to restore cellular homeostasis by optimizing the cellular response to stress. Its activity is dependent on the cellular context and the type as well as intensity of the stress stimuli.

Signal recognition particles

Universally conserved ribonucleoproteins that recognize and target specific proteins to the endoplasmic reticulum.

ER-associated degradation

The cellular pathway that targets misfolded proteins of the endoplasmic reticulum (ER) for ubiquitylation and subsequent degradation by the proteasome.

Electron transport chain

(ETC). A series of complexes within the inner mitochondrial membrane that shuttle electrons from NADH and FADH2 to molecular oxygen.

Enzymatic maximal velocity

(Vmax). The reaction rate when an enzyme is fully saturated by substrate.

Iron–sulphur (Fe–S) clusters

Molecular ensembles of iron and sulfide, often found as components of electron transfer proteins. The ferredoxin proteins are the most common iron–sulfide clusters in nature.

Pyruvate

The conjugate base, CH3COCOO−, of pyruvic acid is a key intermediate in several metabolic pathways throughout the cell.

Superoxide dismutases

A family of enzymes that catalyse the dismutation of the superoxide (O2−) radical into molecular oxygen or hydrogen peroxide.

Telomerase

A ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3′ end of a region of repetitive sequences at each end of chromosomes (telomeres).

Essential electrochemical gradient

A gradient of electrochemical potential, usually for an ion that can move across membranes.

Ubisemiquinone

Ubiquinol is the reduced form of coenzyme Q10 that is oxidized by mitochondrial complex III to the partially reduced form ubisemiquinone and subsequently to the fully oxidized ubiquinone. Ubisemiquionone is a highly unstable free radical that can donate electrons to molecular oxygen to generate superoxide.

Lipid droplets

Lipid-rich storage organelles that regulate the storage and hydrolysis of neutral lipids. They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance.

Pentose phosphate pathway

A predominantly anabolic pathway parallel to glycolysis that generates NADPH and precursors for nucleotide synthesis.

Leigh syndrome

A neurological disorder characterized by progressive loss of mental and motor abilities.

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Lee, P., Chandel, N.S. & Simon, M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol 21, 268–283 (2020). https://doi.org/10.1038/s41580-020-0227-y

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