Abstract
Most manipulations that extend lifespan also increase resistance to various stress factors and environmental cues in a range of animals from yeast to mammals. However, the underlying molecular mechanisms regulating stress resistance during aging are still largely unknown. Here we identify Krüppel-like factor 1 (KLF-1) as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage L3 to D1. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.
Highlights
Most manipulations that extend lifespan increase resistance to various stress factors and environmental cues in a range of animals from yeast to mammals
Xenobiotic detoxification includes activation of drug-metabolizing enzymes (DMEs), which are classified in two main groups: phase I—mainly cytochrome P450 oxidases (CYPs) and phase II—mainly UDPglucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), sulfotransferases, and acetyltransferases, coupled to the activity of phase III transporters that mediate the efflux of metabolic end products out of the cells after the completion of phase II conjugation[3]
We show that upon mild mitochondrial dysfunction and/or oxidative stress, Krüppel-like factor 1 (KLF-1) translocates to the nucleus and activates cyp genes that in different organisms often encode enzymes involved in the xenobiotic detoxification process
Summary
Most manipulations that extend lifespan increase resistance to various stress factors and environmental cues in a range of animals from yeast to mammals. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Increased expression of multiple cyp genes was reported in diverse long-lived C. elegans models, including mitochondrial mutants[6,7]. Interesting, these findings provided just a correlative connection to longevity. We identify Krüppel-like factor 1 (KLF-1) as a major regulator of the detoxification response involved in longevity assurance in Caenorhabditis elegans. We show that upon mild mitochondrial dysfunction and/or oxidative stress, KLF-1 translocates to the nucleus and activates cyp genes that in different organisms often encode enzymes involved in the xenobiotic detoxification process. We further show that a redox-regulated KLF-1 activation coincides with the peak of somatic mitochondrial biogenesis that occurs between L3 and D1 and is essential for the mitohormetic response that dictates longevity
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