NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans
NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans
复制标题
NHR-80 感测线粒体 UPR 以重新连接柠檬酸代谢以促进秀丽隐杆线虫中的脂质积累
DOI：
10.1016/j.celrep.2021.110206
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发表时间：
2022-01-11
期刊：
影响因子：
8.8
通讯作者：
Liang, Bin
中科院分区：
文献类型：
--
作者：
Yang, Rendan;Li, Yamei;Liang, Bin
线粒体被认为是细胞的动力源。线粒体动态平衡失调导致线粒体未折叠蛋白反应(UPRmt)，改变细胞代谢。细胞如何感知UPRmt来重新连接新陈代谢在很大程度上是未知的。在这里，我们证明了柠檬酸/三羧酸(TCA)循环酶ACO-2或IDHA-1(分别编码乌头酸酶和异柠檬酸脱氢酶)的失活会导致柠檬酸积累。在秀丽线虫体内和体外，柠檬酸的积累因此触发了UPRmt，也促进了脂质的积累。转录因子DVE-1与核激素受体NHR-80的启动子结合，反式激活其表达。然后，NHR-80上调脂肪生成和脂肪积累，转移多余的柠檬酸用于脂肪生成，并以三酰甘油的形式储存在脂滴中。DVE-1或NHR-80的失活可完全消除柠檬酸诱导的脂质堆积。因此，我们的工作发现了一个DVE-1-NHR-80-脂生轴，将线粒体应激信号的传递与脂代谢联系起来。
Mitochondria are known as the powerhouse of the cell. Dysfunction of mitochondria homeostasis induces the mitochondrial unfolded protein response (UPRmt), altering cellular metabolism. How cells sense the UPRmt to rewire metabolism is largely unknown. Here, we show that inactivation of either the citric/tricarboxylic acid (TCA) cycle enzymes aco-2 or idha-1, which encode aconitase and isocitrate dehydrogenase respectively, leads to citrate accumulation. In Caenorhabditis elegans, both in vitro and in vivo, citrate accumulation consequently triggers the UPRmt and also promotes lipid accumulation. The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression. NHR-80 then upregulates lipogenesis and lipid accumulation, shifting excess citrate for use in lipogenesis and for storage as triacylglycerol in lipid droplets. Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation. Therefore, our work uncovers a DVE-1-NHR-80-lipogenesis axis linking the transmission of the mitochondria' stress signal to lipid metabolism.