Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia

被引:179
作者
Bell, Eric L.
Klimova, Tatyana A.
Eisenbart, James
Schumacker, Paul T.
Chandel, Navdeep S.
机构
[1] Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA
[2] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA
关键词
D O I
10.1128/MCB.02265-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span.
引用
收藏
页码:5737 / 5745
页数:9
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