Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
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DOI：
10.1083/jcb.201702058
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发表时间：
2017-07-03
期刊：
影响因子：
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通讯作者：
Auwerx J
中科院分区：
文献类型：
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作者：
Quirós PM;Prado MA;Zamboni N;D'Amico D;Williams RW;Finley D;Gygi SP;Auwerx J
线粒体应激激活一致的线粒体核反应，以保护和修复线粒体功能。基罗斯等人。评估了四种应激源下哺乳动物细胞的转录组、蛋白质组和代谢组，并结合群体遗传分析和体内研究，表明 ATF4 协调线粒体应激反应。线粒体应激激活线粒体核反应，以保护和修复线粒体功能并使细胞代谢适应应激。在用四种线粒体应激源处理的哺乳动物细胞中使用多组学方法，我们确定激活转录因子 4 (ATF4) 是应激反应的主要调节因子。令人惊讶的是，ATF5 介导的经典线粒体未折叠蛋白反应基因并未被激活。相反，ATF4 会激活细胞保护基因的表达，从而通过激活整合应激反应 (ISR) 来重新编程细胞代谢。线粒体应激通过减少线粒体核糖体蛋白、抑制线粒体翻译以及将 ISR 的激活与线粒体功能的减弱耦合来促进局部蛋白抑制反应。通过反式表达数量性状基因座分析，我们提供了支持 Fh1 在哺乳动物中控制 Atf4 表达中作用的遗传证据。利用患有线粒体疾病的小鼠和人类的基因表达数据，我们发现 ATF4 通路在线粒体应激时在体内被激活。我们的数据说明了多组学方法在表征复杂细胞网络方面的价值，并提供了一种多功能资源来识别线粒体相关疾病的新调节因子。
Mitochondrial stress activates a concerted mitonuclear response to safeguard and repair mitochondrial function. Quirós et al. assessed the transcriptome, proteome, and metabolome of mammalian cells under four types of stressors and combine population genetic analyses and in vivo studies to show that ATF4 coordinates the mitochondrial stress response. Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.