HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells
HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells
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DOI：
10.1016/j.cell.2007.01.047
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发表时间：
2007-04-06
期刊：
影响因子：
64.5
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Fukuda, Ryo;Zhang, Huafeng;Semenza, Gregg L.
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.
