线粒体-胞质翻译平衡调控长寿通路
2020-02-25   阅读:486   来源:细胞

近日,荷兰阿姆斯特丹大学Riekelt H. Houtkooper及其研究小组的最新工作发现了一个保守的线粒体-胞质翻译平衡,其联系着两条长寿通路。2020年2月20日,《细胞—代谢》杂志在线发表了这项成果。

研究人员在小鼠群体遗传学中发现线粒体和胞质核糖体蛋白(RP)的非干预性自然相关,这表明了翻译的平衡。通过mrps-5 RNAi抑制秀丽隐杆线虫的线粒体翻译从而抑制了胞质翻译。蛋白质组学与转录组学的整合结果表明,这种抑制作用专一地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。研究人员发现药理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也是保守的。
 
最后,研究人员将这一发现拓展至体内,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一个atf-5/ATF4依赖性级联反应,从而导致对细胞质翻译的协同抑制,这可用于延长寿命。
 
据悉,在细胞质或线粒体中减慢翻译是一种保守的长寿机制。
 
附:英文原文

Title: A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways

Author: Marte Molenaars, Georges E. Janssens, Evan G. Williams, Aldo Jongejan, Jiayi Lan, Sylvie Rabot, Fatima Joly, Perry D. Moerland, Bauke V. Schomakers, Marco Lezzerini, Yasmine J. Liu, Mark A. McCormick, Brian K. Kennedy, Michel van Weeghel, Antoine H.C. van Kampen, Ruedi Aebersold, Alyson W. MacInnes, Riekelt H. Houtkooper

Issue&Volume: 2020-02-20

Abstract: Slowing down translation in either the cytosol or the mitochondria is a conservedlongevity mechanism. Here, we found a non-interventional natural correlation of mitochondrialand cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting atranslational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomicsrevealed that this inhibition specifically reduced translational efficiency of mRNAsrequired in growth pathways while increasing stress response mRNAs. The repressionof 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 balanceto be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologicallywith doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. Thesedata 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.

DOI: 10.1016/j.cmet.2020.01.011

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