HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
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DOI：
10.1016/j.cmet.2006.02.002
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发表时间：
2006-03-01
期刊：
影响因子：
29
通讯作者：
Dang, CV
中科院分区：
文献类型：
--
作者：
Kim, JW;Tchernyshyov, I;Dang, CV
HIF-1激活糖酵解基因被认为是通过增加葡萄糖到丙酮酸和随后到乳酸的转化来适应缺氧代谢的关键。我们发现HIF-1还通过直接反式激活编码丙酮酸脱氢酶激酶1 （PDK1）的基因，积极地抑制三羧酸循环（TCA）的代谢，PDK1灭活TCA循环酶丙酮酸脱氢酶（PDH），该酶将丙酮酸转化为乙酰辅酶a。在缺氧HIF-1 α缺失的细胞中强迫PDK1表达增加ATP水平，减弱缺氧ROS的产生，并从缺氧诱导的细胞凋亡中拯救这些细胞。这些研究揭示了缺氧诱导的代谢开关，将葡萄糖代谢物从线粒体分流到糖酵解，以维持ATP的产生并防止有毒ROS的产生。
Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1)-PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1 alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.