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.

中文翻译：

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保守的线粒体-细胞质平移平衡联系了两条长寿途径。

在细胞质或线粒体中减慢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线粒体和胞质核糖体蛋白（RPs）的非干预性自然相关性，表明了翻译的平衡。通过mrps-5 RNAi抑制秀丽隐杆线虫的线粒体翻译抑制了胞质翻译。与蛋白质组学整合的转录组学揭示了这种抑制作用特别降低了生长途径中所需的mRNA的翻译效率，同时增加了应激反应mRNA的表达。mrps-5 RNAi对胞质翻译的抑制和寿命的延长取决于atf-5 / ATF4，并且不依赖于代谢表型。我们发现在药理学上用强力霉素抑制线粒体翻译后，翻译平衡在哺乳动物细胞中得以保留。最后，将其扩展到体内，强力霉素抑制了无菌小鼠肝脏中的胞质翻译。这些数据表明，抑制线粒体翻译会启动atf-5 / ATF4依赖性级联反应，从而导致细胞溶质翻译的协同抑制，这可能是为了延长寿命。