PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells
PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells
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DOI：
10.1073/pnas.0808801106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Allan, Bernard B.
中科院分区：
文献类型：
--
作者：
O'Hagan, Kathleen A.;Cocchiglia, Sinead;Allan, Bernard B.
线粒体的生物发生是对细胞ATP需求增加的反应。线粒体电子传递链需要分子氧来产生ATP。因此，线粒体生物发生后ATP生成的增加导致需氧量增加，这必须与氧供应的相应增加相匹配。我们发现，过氧化物酶体增殖物激活受体-γ共激活因子1 α（PGC-1 α）的过度表达增加了原代骨骼肌细胞中线粒体的生物合成，导致一组已知受二聚缺氧诱导因子（HIF）调控的基因表达增加，HIF是缺氧适应性反应的主要调节因子。在生理氧浓度下，HIF靶基因的PGC-1 α依赖性诱导不是通过HIF的转录共激活或HIF-1 α mRNA的上调，而是通过HIF-1 α蛋白的稳定。其发生是由于线粒体生物合成后氧消耗增加导致的细胞内缺氧。因此，我们提出，在生理氧浓度下，PGC-1 α通过调节细胞内氧可用性与HIF信号传导偶联，使细胞和组织在线粒体生物合成后增加的氧需求与增加的氧供应相匹配。
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 1 alpha (PGC-1 alpha), 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-1 alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1 alpha mRNA but through HIF-1 alpha 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-1 alpha 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.