Division of Molecular and Life Science, School of Interdisciplinary Bioscience and Bioengineering, and World Class University Information Technology Convergence Engineering, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea.
Curr Biol. 2010 Dec 7;20(23):2131-6. doi: 10.1016/j.cub.2010.10.057. Epub 2010 Nov 18.
A mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice, but the underlying mechanism is unknown. One environmental condition that reduces rates of respiration is hypoxia (low oxygen). Thus, it is possible that mechanisms that sense oxygen play a role in the longevity response to reduced respiration. The hypoxia-inducible factor HIF-1 is a highly conserved transcription factor that activates genes that promote survival during hypoxia. In this study, we show that inhibition of respiration in C. elegans can promote longevity by activating HIF-1. Through genome-wide screening, we found that RNA interference (RNAi) knockdown of many genes encoding respiratory-chain components induced hif-1-dependent transcription. Moreover, HIF-1 was required for the extended life spans of clk-1 and isp-1 mutants, which have reduced rates of respiration. Inhibiting respiration appears to activate HIF-1 by elevating the level of reactive oxygen species (ROS). We found that ROS are increased in respiration mutants and that mild increases in ROS can stimulate HIF-1 to activate gene expression and promote longevity. In this way, HIF-1 appears to link respiratory stress in the mitochondria to a nuclear transcriptional response that promotes longevity.
线粒体呼吸的轻度抑制可以延长许多生物体的寿命，包括酵母、蠕虫、苍蝇和老鼠，但潜在的机制尚不清楚。一种降低呼吸速率的环境条件是缺氧（低氧）。因此，感知氧气的机制可能在对呼吸减少的长寿反应中发挥作用。缺氧诱导因子 HIF-1 是一种高度保守的转录因子，可激活在缺氧期间促进生存的基因。在这项研究中，我们表明，通过激活 HIF-1，秀丽隐杆线虫呼吸的抑制可以促进寿命延长。通过全基因组筛选，我们发现许多编码呼吸链成分的基因的 RNA 干扰 (RNAi) 敲低诱导了 hif-1 依赖性转录。此外，HIF-1 是 clk-1 和 isp-1 突变体延长寿命所必需的，这些突变体的呼吸速率降低。抑制呼吸似乎通过提高活性氧 (ROS) 的水平来激活 HIF-1。我们发现呼吸突变体中的 ROS 增加，并且轻度增加的 ROS 可以刺激 HIF-1 激活基因表达并促进长寿。通过这种方式，HIF-1 似乎将线粒体中的呼吸应激与促进长寿的核转录反应联系起来。
