Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol
Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol
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DOI：
10.1038/nature14951
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发表时间：
2015-08-27
期刊：
影响因子：
64.8
通讯作者：
Chacinska, Agnieszka
中科院分区：
文献类型：
--
作者：
Wrobel, Lidia;Topf, Ulrike;Chacinska, Agnieszka
线粒体蛋白质组大部分来源于核基因，在细胞质中合成后转运到线粒体中。维持蛋白质输入和分选特异性的复杂机制包括负责将前体蛋白质转移到基质中的TIM23转座酶，以及膜间空间蛋白质生物发生所需的线粒体膜间空间输入和组装（MIA）机制。线粒体蛋白分选途径的功能障碍导致特定底物蛋白的减少，随后是细胞器的系统性病理和有机体死亡（1-4）。线粒体前体蛋白在细胞质中积累所引起的细胞反应主要是未知的。在这里，我们提出了一个全面的变化，在细胞转录组和蛋白质组响应线粒体输入缺陷和前体过度积累应激。通过抑制蛋白质合成和激活蛋白酶体（细胞蛋白质清除的主要机器），确定了保护细胞免受线粒体生物发生缺陷的途径。蛋白酶体活性与细胞质中线粒体前体蛋白错位的数量成比例调节。我们认为这种由蛋白错靶激活的未折叠蛋白反应（UPRam）对细胞有益。UPRam提供了一种手段，可以缓冲线粒体蛋白质进口生理减缓的后果，并抵消由线粒体功能障碍引起或促成的病理。
Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death(1-4). The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.