Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia
Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia
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DOI：
10.1128/mcb.02265-06
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
--
作者：
Bell, Eric L.;Klimova, Tatyana A.;Chandel, Navdeep S.
生理性缺氧可延长培养中人类细胞的复制寿命。在这里，我们报告说，低氧条件下复制寿命的延长与原代人肺成纤维细胞中线粒体活性氧（ROS）的增加有关。线粒体 ROS 的产生对于转录因子缺氧诱导因子 (HIF) 的缺氧激活是必需的。复制寿命的缺氧延长被显性负性 HIF 消除。 HIF 足以诱导端粒酶逆转录酶 mRNA 和端粒酶活性并延长复制寿命。此外，通过 RNA 干扰下调 von Hippel-Lindau 肿瘤抑制蛋白可增加 HIF 活性并延长常氧条件下的复制寿命。这些发现提供了遗传证据，表明缺氧利用线粒体 ROS 作为信号分子来激活 HIF 依赖性的复制寿命延长。
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.