Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, D-50931, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), D-50931, Cologne, Germany.
Nat Commun. 2019 Jul 25;10(1):3323. doi: 10.1038/s41467-019-11275-w.
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.
大多数延长寿命的操作也会增加从酵母到哺乳动物等各种动物对各种应激因素和环境线索的抵抗力。然而，调节衰老过程中应激抗性的潜在分子机制在很大程度上仍然未知。在这里，我们将 Krüppel 样因子 1（KLF-1）鉴定为一种细胞保护反应的介质，该反应决定了由减少线粒体功能引起的寿命延长。一种氧化还原调节的 KLF-1 激活和向核内转移与体细胞线粒体生物发生的峰值同时发生，该峰值发生在从幼虫阶段 L3 到 D1 的转变期间。我们进一步表明，KLF-1 激活参与外来化合物解毒程序的基因，并确定细胞色素 P450 氧化酶，即 KLF-1 的主要效应物，作为线粒体突变体的长寿保证因素。总的来说，这些发现强调了外来化合物解毒在mitohormetic 、长寿保证途径中的重要性，并将 KLF-1 鉴定为协调这种反应的核心因素。
