Defining hypoxia: a systems view of VO2, glycolysis, energetics, and intracellular PO2
Abstract
The necessity for defining hypoxia as O2-limited energy flux rather than low partial pressure is explored from a systems perspective. Oxidative phosphorylation, the Krebs cycle, glycolysis, substrate supply, and cell energetics interact as subsystems; the set point is a match between ATP demand and aerobic ATP production. To this end the transport subsystem must match the transcapillary and mitochondrial O2 fluxes. High transcapillary O2 flux requires intracellular PO2 in the range 1-10 Torr. In this range the O2 drive on electron transport must be compensated by adaptive changes in the phosphorylation and redox drives. Thus the metabolic subsystem supports diffusive O2 transport by maintaining O2 flux at intracellular partial pressures required for O2 release from blood. Since responses to stress are distributed according to the state of the entire system, several simultaneous metabolic measurements, including intracellular PO2 (or a known direction of change in intracellular PO2) and the O2 dependence of a measurable function are required to judge the adequacy of O2 supply. ATP demand and aerobic capacity must also be evaluated, because the hypoxic threshold depends on the ratio of ATP demand to aerobic capacity. The application and limitation of commonly used criteria of hypoxia are discussed, and a more precise terminology is proposed.
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Reduced oxygen tension activates a conserved hypoxic signaling network centered on hypoxia-inducible factors (HIFs).
“Reduced oxygen tension activates a conserved hypoxic signaling network centered on hypoxia-inducible factors (HIFs)”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [1]
Both physiological and pathological states can transiently disrupt the equilibrium between oxygen supply and demand, resulting in tissue and cellular hypoxia.
“Nevertheless, both physiological and pathological states can transiently disrupt the equilibrium between oxygen supply and demand, resulting in tissue and cellular hypoxia”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [1]
The hypoxia response features extensive transcriptional reprogramming aimed at preserving cellular integrity under low-oxygen conditions.
“This response features extensive transcriptional reprogramming aimed at preserving cellular integrity under low-oxygen conditions”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [1]
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HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
“At the cellular level, insufficient oxygen availability activates a conserved signaling network known as the adaptive response to hypoxia [1,2] (see Table 1).”
- Authors
- Connett, R. J., Honig, C. R., Gayeski, T. E., & Brooks, G. A.
- Affiliations
- University of Rochester (US)
- ORCID
- Brooks, G. A.
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 1990-03-01
- Volume
- 68
- Issue
- 3
- Pages
- 833-842
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- OpenAlex
- W1892024851
- Cited by
- 389
- References
- 1
- Citations by year
- 2026: 4 · 2024: 5 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 13 · 2019: 10 · 2018: 14 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 8 · 2013: 11 · 2012: 18
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Applied Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ar036154-05)
- National Heart, Lung, and Blood Institute (HL03290)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-36154)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Health Sciences › Medicine › Surgery › Biomedical and Chemical Research
- Keywords
- hypoxia, oxygen consumption, glycolysis, oxidative phosphorylation, TCA cycle, ATP demand, cardiorespiratory fitness, oxygen transport
- MeSH terms
- Adenosine Triphosphate, Animals, Hypoxia, Energy Metabolism, Glycolysis, Humans, Oxygen Consumption
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