HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells

被引：1011

作者：

Fukuda, Ryo

Zhang, Huafeng

Kim, Jung-whan

Shimoda, Larissa

Dang, Chi V.

Semenza, Gregg L. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Vasc Biol Program, Inst Cell Engn, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA

来源：

CELL | 2007年 / 129卷 / 01期

关键词：

D O I：

10.1016/j.cell.2007.01.047

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：111 / 122

页数：12

共 43 条

[21]

Kwast KE, 1998, J EXP BIOL, V201, P1177

[22] FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor [J].