HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia

被引：2917

作者：

Kim, JW

Tchernyshyov, I

Semenza, GL

Dang, CV ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Grad Program Pathobiol, Dept Med, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Vasc Biol Program, Inst Cell Engn, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

来源：

CELL METABOLISM | 2006年 / 3卷 / 03期

关键词：

D O I：

10.1016/j.cmet.2006.02.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：177 / 185

页数：9

共 25 条

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