Cited by 1,272Cancer, Hypoxia, and MetabolismRedox biology and oxidative stressErythropoietin and Anemia Treatment

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Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

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Lee, Pearl, Chandel, Navdeep S., Simon, M. Celeste·2020·Nature Reviews Molecular Cell Biology

DOI 10.1038/s41580-020-0227-yPMC PMC7222024

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Abstract

Molecular oxygen (O 2) 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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Hernansanz-Agustín, P. et al. Mitochondrial Na+ import controls oxidative phosphorylation and hypoxic redox signalling. bioRxiv https://doi.org/10.1101/385690 (2018). · DOI

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Authors: Lee, P., Chandel, N. S., & Simon, M. C.
Affiliations: University of Pennsylvania (US)
Northwestern University (US)
Corresponding author: Lee, Pearl
Chandel, Navdeep S.
Simon, M. Celeste
ORCID: Lee, Pearl
Chandel, Navdeep S.
Simon, M. Celeste
Venue: Nature Reviews Molecular Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2020-03-06
Volume: 21
Issue: 5
Pages: 268-283
ISSN: 1471-0072 (ISSN-L)
1471-0080
DOI: 10.1038/s41580-020-0227-y
PMC: PMC7222024
OpenAlex: W3009721059
Cited by: 1,272
References: 233
Citations by year: 2026: 207 · 2025: 275 · 2024: 209 · 2023: 201 · 2022: 186 · 2021: 137 · 2020: 55
FWCI: 14.94
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Molecular Cell Biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (F32CA217185, P01CA104838, R35CA197532, R01CA158301, R35CA220483)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR053461)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords: hypoxia, hypoxia-inducible factor, cellular adaptation, oxygen sensing, energy metabolism, glycolysis, angiogenesis, reactive oxygen species, mitochondrial respiration, nutrient uptake, protein synthesis, cancer, cardiovascular disease, inflammation, wound healing, transcriptional response
MeSH terms: Adenosine Triphosphate, Energy Metabolism, Humans, Mitochondria, Oxygen, Signal Transduction, Cell Hypoxia, Reactive Oxygen Species, Oxidative Stress

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