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Cited by 1,225Cancer, Hypoxia, and MetabolismMitochondrial Function and PathologyRedox biology and oxidative stress

HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells

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Fukuda, Ryo, Zhang, Huafeng, Kim, Jung-whan, Shimoda, Larissa, Dang, Chi V., Semenza, Gregg L.·2007·Cell
DOI 10.1016/j.cell.2007.01.047
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Abstract

O(2) is the ultimate electron acceptor for mitochondrial respiration, a process catalyzed by cytochrome c oxidase (COX). In yeast, COX subunit composition is regulated by COX5a and COX5b gene transcription in response to high and low O(2), respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O(2) regulated. Under conditions of reduced O(2) availability, hypoxia-inducible factor 1 (HIF-1) reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation. The effects of manipulating COX4 subunit expression on COX activity, ATP production, O(2) consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O(2) concentrations. Thus, mammalian cells respond to hypoxia by altering COX subunit composition, as previously observed in yeast, but by a completely different molecular mechanism.

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  • HIF-1 promotes a subunit switch in cytochrome c oxidase 4 from COX4-1 to COX4-2 during hypoxia, improving efficiency of electron transport at complex IV.

    “This transcription factor also promotes a subunit switch in cytochrome c oxidase 4 or COX4 from 4-1 to 4-2 during hypoxia, which improves the efficiency of electron transport at complex IV (143).”

    From Redox regulation of mitochondrial function (2012) · cites this paper as [143]

  • The human PKM2 gene contains a candidate HRE within the first intron with the antisense HIF-1 binding site 5′-ACGTG-3′ followed by a 5′-CACA-3′ sequence.

    “Analysis of the human PKM2 gene sequence revealed a candidate HRE within the first intron containing (on the antisense strand) the HIF-1 binding site 5′-ACGTG-3′ followed by a 5′-CACA-3′ sequence (Figure 1C), which is found in many HREs (Fukuda et al., 2007).”

    From Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1 (2011) · cites this paper as Fukuda et al., 2007

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Authors
Fukuda, R., Zhang, H., Kim, J.-W., Shimoda, L., Dang, C. V., & Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
Semenza, Gregg L.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2007-04
Volume
129
Issue
1
Pages
111-122
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2007.01.047
OpenAlex
W2054987125
Cited by
1,225
References
44
Citations by year
2026: 45 · 2025: 61 · 2024: 49 · 2023: 54 · 2022: 70 · 2021: 74 · 2020: 89 · 2019: 59 · 2018: 60 · 2017: 63 · 2016: 66 · 2015: 73 · 2014: 64 · 2013: 59 · 2012: 78
FWCI
23.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
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, cytochrome c oxidase, hypoxia, oxygen regulation, Lon protease, mitochondrial respiration, reactive oxygen species, ATP production, transcriptional regulation
MeSH terms
Aerobiosis, Animals, Cell Line, Cells, Cultured, Electron Transport Complex IV, Embryo, Mammalian, Fibroblasts, HeLa Cells, Humans, Isoenzymes, Pulmonary Artery, RNA, Messenger, Cell Hypoxia, Gene Expression Regulation, Enzymologic, Cell Respiration, Response Elements, Protein Subunits, Myocytes, Smooth Muscle, Cell Line, Tumor, Protease La, Mice, Hypoxia-Inducible Factor 1

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