PGC-1alpha is coupled to HIF-1alpha-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells.
Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1alpha mRNA but through HIF-1alpha protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1alpha is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.
O'Hagan
Kathleen A
KA
Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Cocchiglia
Sinead
S
Zhdanov
Alexander V
AV
Tambuwala
Murtaza M
MM
Tambawala
Murtaza M
MM
Cummins
Eoin P
EP
Monfared
Mona
M
Agbor
Terence A
TA
Garvey
John F
JF
Papkovsky
Dmitri B
DB
Taylor
Cormac T
CT
Allan
Bernard B
BB
D000818:Animals; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
C497442:HIF1A protein, human; D006360:Heat-Shock Proteins; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D010100:Oxygen