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

Ryo Fukuda; Huafeng Zhang; Jung whan Kim; Larissa Shimoda; Chi V. Dang; Gregg L L. Semenza

doi:10.1016/j.cell.2007.01.047

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

Ryo Fukuda, Huafeng Zhang, Jung whan Kim, Larissa Shimoda, Chi V. Dang, Gregg L L. Semenza

School of Medicine

Research output: Contribution to journal › Article › peer-review

806 Scopus citations

Abstract

O₂ 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 O₂, respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O₂ regulated. Under conditions of reduced O₂ 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, O₂ consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O₂ concentrations. Thus, mammalian cells respond to hypoxia by altering COX subunit composition, as previously observed in yeast, but by a completely different molecular mechanism.

Original language	English (US)
Pages (from-to)	111-122
Number of pages	12
Journal	Cell
Volume	129
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2007.01.047
State	Published - Apr 6 2007

Keywords

CELLBIO
HUMDISEASE
RNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2007.01.047

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title = "HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells",

abstract = "O2 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 O2, respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O2 regulated. Under conditions of reduced O2 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, O2 consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O2 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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author = "Ryo Fukuda and Huafeng Zhang and Kim, {Jung whan} and Larissa Shimoda and Dang, {Chi V.} and Semenza, {Gregg L L.}",

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doi = "10.1016/j.cell.2007.01.047",

language = "English (US)",

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T1 - HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells

AU - Fukuda, Ryo

AU - Zhang, Huafeng

AU - Kim, Jung whan

AU - Shimoda, Larissa

AU - Dang, Chi V.

AU - Semenza, Gregg L L.

PY - 2007/4/6

Y1 - 2007/4/6

N2 - O2 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 O2, respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O2 regulated. Under conditions of reduced O2 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, O2 consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O2 concentrations. Thus, mammalian cells respond to hypoxia by altering COX subunit composition, as previously observed in yeast, but by a completely different molecular mechanism.

AB - O2 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 O2, respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O2 regulated. Under conditions of reduced O2 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, O2 consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O2 concentrations. Thus, mammalian cells respond to hypoxia by altering COX subunit composition, as previously observed in yeast, but by a completely different molecular mechanism.

KW - CELLBIO

KW - HUMDISEASE

KW - RNA

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JO - Cell

JF - Cell

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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