The DOI matches its Crossref record; 110 of the 113 references it cites were found in a registry or an index.
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1
Abstract
The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at Complex III, results in the increased generation of ROS (reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl-CoA. In combination with the hypoxia-induced expression of LDHA (lactate dehydrogenase A), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of NADH and FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions. Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.
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In the citing paper
“For example, H2O2-induced oxidation of a cysteine residue located in its catalytic site precisely and rapidly inhibits tyrosine phosphatase (278, 315).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [278]
In the citing paper
“Mitochondria are essential regulators of cellular bioenergetics that respond to changes in environmental stimuli, such as hormones, nutrients, and oxygen tension (47, 94, 99, 109, 290, 301, 385).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [385]
In the citing paper
“HIF-1 coordinately upregulates many genes to regulate metabolism, energy production, and mitochondrial function (385).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [385]
In the citing paper
“Nonetheless, experimental evidence suggests that enhanced ROS production is not a sustained event in hypoxia (69, 385).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [385]
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HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
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Self-citationProgenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1
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Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
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Metadata
- Authors
- Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- ORCID
- Semenza, Gregg L.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2007-06-13
- Volume
- 405
- Issue
- 1
- Pages
- 1-9
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1799768544
- Cited by
- 541
- References
- 113
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 15 · 2023: 16 · 2022: 19 · 2021: 37 · 2020: 25 · 2019: 27 · 2018: 29 · 2017: 27 · 2016: 29 · 2015: 29 · 2014: 29 · 2013: 36 · 2012: 37
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hv28180-13-0-0)
- National Heart, Lung, and Blood Institute (N01 HV-28180, R01HL055338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- HIF-1, mitochondrial respiration, cytochrome c oxidase, PDK1, pyruvate dehydrogenase, LDHA, reactive oxygen species, electron transport chain, TCA cycle, Lon protease, oxygen homeostasis
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Electron Transport Complex IV, Electron Transport, Gene Expression Regulation, Glucose, Glycolysis, Homeostasis, Mitochondria, Oxidative Phosphorylation, Oxygen, Protein Kinases, Protein Serine-Threonine Kinases, Cell Respiration, Hypoxia-Inducible Factor 1
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