HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells.
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.
Fukuda
Ryo
R
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhang
Huafeng
H
Kim
Jung-whan
JW
Shimoda
Larissa
L
Dang
Chi V
CV
Semenza
Gregg L
GL
D000332:Aerobiosis; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D019069:Cell Respiration; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle; D049070:Protease La / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D012333:RNA, Messenger; D020218:Response Elements
D051793:Hypoxia-Inducible Factor 1; D007527:Isoenzymes; D021122:Protein Subunits; D012333:RNA, Messenger; D003576:Electron Transport Complex IV; D049070:Protease La