Cited by 542Cancer, Hypoxia, and MetabolismMitochondrial Function and PathologyRedox biology and oxidative stress

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Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1

Semenza, Gregg L.·2007·Biochemical Journal

DOI 10.1042/bj20070389

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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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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
DOI: 10.1042/bj20070389
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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Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1

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