Oligomycin inhibits HIF-1α expression in hypoxic tumor cells
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key regulator of cellular responses to reduced oxygen availability. The contribution of mitochondria in regulation of HIF-1alpha in hypoxic cells has received recent attention. We demonstrate that inhibition of electron transport complexes I, III, and IV diminished hypoxic HIF-1alpha accumulation in different tumor cell lines. Hypoxia-induced HIF-1alpha accumulation was not prevented by the antioxidants Trolox and N-acetyl-cysteine. Oligomycin, inhibitor of F(0)F(1)-ATPase, prevented hypoxia-induced HIF-1alpha protein accumulation and had no effect on HIF-1alpha induction by hypoxia-mimicking agents desferrioxamine or dimethyloxalylglycine. The inhibitory effect of mitochondrial respiratory chain inhibitors and oligomycin on hypoxic HIF-1alpha content was pronounced in cells exposed to hypoxia (1.5% O(2)) but decreased markedly when cells were exposed to severe oxygen deprivation (anoxia). Taken together, these results do not support the role for mitochondrial reactive oxygen species in HIF-1alpha regulation, but rather suggest that inhibition of electron transport chain and impaired oxygen consumption affect HIF-1alpha accumulation in hypoxic cells indirectly via effects on prolyl hydroxylase function.
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Treatment with mitochondrial inhibitors is associated with reduced HIF-1α protein levels under hypoxia.
“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 [370]
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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
- Authors
- Gong, Y., & Agani, F. H.
- Affiliations
- Case Western Reserve University (US)
- ORCID
- Gong, Yanqing
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2005-05
- Volume
- 288
- Issue
- 5
- Pages
- C1023-C1029
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2162596812
- Cited by
- 54
- References
- 7
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 6 · 2019: 1 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 4 · 2012: 3
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns041309-03)
- National Institute of Neurological Disorders and Stroke (NS41309)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- oligomycin, HIF-1α, hypoxia, cancer cells, mitochondrial electron transport chain, prolyl hydroxylase, reactive oxygen species, anoxia, oxygen consumption, deferoxamine, dimethyloxalylglycine, antioxidants
- MeSH terms
- Acetylcysteine, Amino Acids, Dicarboxylic, Chromans, Deferoxamine, DNA-Binding Proteins, Electron Transport, Enzyme Inhibitors, Proton-Translocating ATPases, Humans, Mitochondria, Nuclear Proteins, Oligomycins, Transcription Factors, Tumor Cells, Cultured, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Reactive Oxygen Species, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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