The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.
Hypoxic but not anoxic stabilization of HIF-1α requires mitochondrial reactive oxygen species
Abstract
The molecular mechanisms by which cells detect hypoxia (1.5% O2), resulting in the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) protein remain unclear. One model proposes that mitochondrial generation of reactive oxygen species is required to stabilize HIF-1alpha protein. Primary evidence for this model comes from the observation that cells treated with complex I inhibitors, such as rotenone, or cells that lack mitochondrial DNA (rho(0)-cells) fail to generate reactive oxygen species or stabilize HIF-1alpha protein in response to hypoxia. In the present study, we investigated the role of mitochondria in regulating HIF-1alpha protein stabilization under anoxia (0% O2). Wild-type A549 and HT1080 cells stabilized HIF-1alpha protein in response to hypoxia and anoxia. The rho(0)-A549 cells and rho(0)-HT1080 cells failed to accumulate HIF-1alpha protein in response to hypoxia. However, both rho(0)-A549 and rho(0)-HT1080 were able to stabilize HIF-1alpha protein levels in response to anoxia. Rotenone inhibited hypoxic, but not anoxic, stabilization of HIF-1alpha protein. These results indicate that a functional electron transport chain is required for hypoxic but not anoxic stabilization of HIF-1alpha protein.
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In the citing paper
“Under severe hypoxia or anoxia, cytosolic oxygen levels may remain insufficient to restore prolyl hydroxylase activity even following mitochondrial inhibition, thereby limiting HIF-1α destabilization [369].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [369]
In the citing paper
“treatment with mitochondrial inhibitors - including rotenone, oligomycin, the complex I inhibitor IACS-010759, mitochondrial uncouplers, and clinically approved agents such as atovaquone and metformin, has been associated with reduced HIF-1α protein levels under hypoxia [[369], [370], [371], [372], [373], [374], [375]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [369]
In the citing paper
“Specifically, mitochondrial ROS contribute to HIF-1α accumulation independently of respiratory activity, highlighting the paradoxical role of mitochondria in regulating hypoxic signaling [369,377].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [369]
Citations
Cites
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HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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Self-citationMitochondrial reactive oxygen species trigger hypoxia-induced transcription
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Cited by
Sorted by citations
Mitochondrial formation of reactive oxygen species
Turrens, J. F. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.049478 · Cited by 5,084
ROS signalling in the biology of cancer
Moloney, J. N., & Cotter, T. G. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.05.023 · Cited by 2,030
Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing
Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., Simon, M. C., Hammerling, U., & Schumacker, P. T. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.001 · Cited by 1,545
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
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Metadata
- Authors
- Schroedl, C., McClintock, D. S., Budinger, G. R. S., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2002-11-01
- Volume
- 283
- Issue
- 5
- Pages
- L922-L931
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- OpenAlex
- W2095062583
- Cited by
- 266
- References
- 39
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 13 · 2020: 4 · 2019: 9 · 2018: 5 · 2017: 14 · 2016: 9 · 2015: 11 · 2014: 8 · 2013: 14 · 2012: 11
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM060472, GM60472-03)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- HIF-1α stabilization, hypoxia, anoxia, mitochondrial reactive oxygen species, electron transport chain, rotenone, mitochondrial DNA deletions, mitochondrial complex I inhibition, A549 cells, HT1080 cells
- MeSH terms
- Adenosine Triphosphate, Animals, Hypoxia, Cell Line, Cricetinae, Humans, Kinetics, Lung, Mitochondria, Oxygen Consumption, Recombinant Proteins, Transcription Factors, Transfection, Cell Hypoxia, Apoptosis, Reactive Oxygen Species, Genes, Reporter, Urothelium, Respiratory Mucosa, Hypoxia-Inducible Factor 1, alpha Subunit
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