Molenaars Marte, Janssens Georges E, Williams Evan G, Jongejan Aldo, Lan Jiayi, Rabot Sylvie, Joly Fatima, Moerland Perry D, Schomakers Bauke V, Lezzerini Marco, Liu Yasmine J, McCormick Mark A, Kennedy Brian K, van Weeghel Michel, van Kampen Antoine H C, Aebersold Ruedi, MacInnes Alyson W, Houtkooper Riekelt H
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
Institute of Molecular Systems Biology, ETH Zurich, Zürich, Switzerland.
Cell Metab. 2020 Mar 3;31(3):549-563.e7. doi: 10.1016/j.cmet.2020.01.011. Epub 2020 Feb 20.
Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.
减缓细胞质或线粒体中的翻译是一种保守的长寿机制。在这里，我们在小鼠群体遗传学中发现了线粒体和细胞质核糖体蛋白（RPs）之间的非干预性自然关联，这表明存在翻译平衡。通过mrps-5 RNA干扰抑制秀丽隐杆线虫中的线粒体翻译会抑制细胞质翻译。转录组学与蛋白质组学相结合表明，这种抑制作用特别降低了生长途径中所需mRNA的翻译效率，同时增加了应激反应mRNA。mrps-5 RNA干扰对细胞质翻译的抑制和寿命的延长依赖于atf-5/ATF4，且与代谢表型无关。我们发现，在用强力霉素药理学抑制线粒体翻译后，哺乳动物细胞中的翻译平衡得以保守。最后，在体内进行扩展研究，强力霉素抑制了无菌小鼠肝脏中的细胞质翻译。这些数据表明，抑制线粒体翻译会启动一个依赖于atf-5/ATF4的级联反应，导致细胞质翻译的协同抑制，这可能是促进长寿的靶点。
