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Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro
Open accessAbstract
Prolyl hydroxylation of hypoxible-inducible factor alpha (HIF-alpha) proteins is essential for their recognition by pVHL containing ubiquitin ligase complexes and subsequent degradation in oxygen (O(2))-replete cells. Therefore, HIF prolyl hydroxylase (PHD) enzymatic activity is critical for the regulation of cellular responses to O(2) deprivation (hypoxia). Using a fusion protein containing the human HIF-1alpha O(2)-dependent degradation domain (ODD), we monitored PHD activity both in vivo and in cell-free systems. This novel assay allows the simultaneous detection of both hydroxylated and nonhydroxylated PHD substrates in cells and during in vitro reactions. Importantly, the ODD fusion protein is regulated with kinetics identical to endogenous HIF-1alpha during cellular hypoxia and reoxygenation. Using in vitro assays, we demonstrated that the levels of iron (Fe), ascorbate, and various tricarboxylic acid (TCA) cycle intermediates affect PHD activity. The intracellular levels of these factors also modulate PHD function and HIF-1alpha accumulation in vivo. Furthermore, cells treated with mitochondrial inhibitors, such as rotenone and myxothiazol, provided direct evidence that PHDs remain active in hypoxic cells lacking functional mitochondria. Our results suggest that multiple mitochondrial products, including TCA cycle intermediates and reactive oxygen species, can coordinate PHD activity, HIF stabilization, and cellular responses to O(2) depletion.
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“As a result, EGLN 1–3 activity and HIF-α stability are affected by iron availability and can be inhibited by Krebs cycle intermediates, including succinate and fumarate, which compete with 2-oxoglutarate”
From Hypoxic control of metastasis (2016) · cites this paper as [18]
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Metadata
- Authors
- Pan, Y., Mansfield, K. D., Bertozzi, C. C., Rudenko, V., Chan, D. A., Giaccia, A. J., & Simon, M. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Pennsylvania (US)
- Stanford Medicine (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-02-01
- Volume
- 27
- Issue
- 3
- Pages
- 912-925
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1800695
- OpenAlex
- W2105236768
- Cited by
- 332
- References
- 59
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 16 · 2023: 15 · 2022: 15 · 2021: 11 · 2020: 14 · 2019: 18 · 2018: 16 · 2017: 14 · 2016: 25 · 2015: 19 · 2014: 18 · 2013: 22 · 2012: 19
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health (CA104838)
- National Cancer Institute (P01CA104838, CA104838)
- Abramson Family Cancer Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- HIF-1α, oxygen-dependent degradation domain, HIF-1α stabilization, cellular redox status, energy metabolism, iron, vitamin C, tricarboxylic acid cycle intermediates, reactive oxygen species, mitochondrial inhibitors, rotenone, myxothiazol, oxygen deprivation, reoxygenation
- MeSH terms
- Animals, Carcinoma, Renal Cell, Electron Transport, Electrophoresis, Polyacrylamide Gel, Energy Metabolism, Gene Expression Regulation, Humans, Hydrogen Peroxide, Hydroxylation, Mitochondria, Oxidation-Reduction, Proline, Procollagen-Proline Dioxygenase, Recombinant Fusion Proteins, RNA, Messenger, Thermodynamics, Uncoupling Agents, Cell Hypoxia, Molecular Mimicry, Protein Transport, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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