Journal
CURRENT BIOLOGY
Volume 20, Issue 23, Pages 2131-2136Publisher
CELL PRESS
DOI: 10.1016/j.cub.2010.10.057
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Funding
- National Institutes of Health (NIH) National Center for Research Resources
- American Heart Association
- NIH [AG01181z6]
- World Class University program [R31-2008-000-10100-0]
- Ministry of Education, Science and Technology [20100009278]
- POSTECH Basic Science Research Institute
- National Research Foundation of Korea [2010-0009278] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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A mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice [1-10], 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 [11, 12]. 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 [1, 4, 13]. 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.
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