HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
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DOI：
10.1016/j.cmet.2006.01.012
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发表时间：
2006-03-01
期刊：
影响因子：
29
通讯作者：
Denko, NC
中科院分区：
文献类型：
--
作者：
Papandreou, I;Cairns, RA;Denko, NC
HIF-1转录因子驱动低氧基因表达的变化，这些变化被认为是对暴露于低氧环境的细胞的适应。例如，HIF-1诱导糖酵解基因的表达。据推测，当低氧不支持线粒体的氧化磷酸化时，增加糖酵解是产生能量所必需的。然而，我们发现，虽然HIF-1刺激糖酵解，它也积极抑制线粒体功能和氧消耗诱导丙酮酸脱氢酶激酶1（PDK 1）。PDK 1磷酸化并抑制丙酮酸脱氢酶使用丙酮酸为线粒体TCA循环提供燃料。这导致线粒体耗氧量下降，并导致细胞内氧张力相对增加。我们通过遗传手段表明，HIF-1依赖性阻断氧利用导致氧可用性增加，当总氧限制时细胞死亡减少，并且响应于缺氧细胞毒素替拉扎明的细胞死亡减少。
The HIF-1 transcription factor drives hypoxic gene expression changes that are thought to be adaptive for cells exposed to a reduced-oxygen environment. For example, HIF-1 induces the expression Of glycolytic genes. It is presumed that increased glycolysis is necessary to produce energy when low oxygen will not support oxidative phosphorylation at the mitochondria. However, we find that while HIF-1 stimulates glycolysis, it also actively represses mitochondrial function and oxygen consumption by inducing pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase from using pyruvate to fuel the mitochondrial TCA cycle. This causes a drop in mitochondrial oxygen consumption and results in a relative increase in intracellular oxygen tension. We show by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.