DOI：10.1038/nature14859 作者：Xiaowen Wang & Xin Jie Chen
摘要 : 线粒体功能障碍和细胞蛋白平衡失败是很多疾病和与年龄相关的病变的特征。
线粒体功能障碍和细胞蛋白平衡失败是很多疾病和与年龄相关的病变的特征。受损的线粒体会通过各种机制(包括能量剥夺)导致细胞死亡。现在，本期Nature上的两篇论文描述了另外一种机制：来自胞质中的核糖体的线粒体蛋白的低效运输。Xiaowen Wang和Xin Jie Chen发现，线粒体损伤会阻断核编码的蛋白向线粒体内的运输，通过触发胞质中他们命名为 “线粒体前体过度积累压力”(mPOS)的通道造成细胞退化。作者还识别出一个由补偿过程(其中大部分与蛋白周转和折叠的调制有关)组成的抗退化网络，它们对抗mPOS，以帮助细胞存活。Agnieszka Chacinska及同事通过对细胞内的转录组和蛋白组变化进行详细分析，研究了对蛋白向线粒体内的运输过程的失常的反应。他们还识别出了保护细胞不受线粒体生源缺陷影响的通道，后者主要涉及通过蛋白酶体机制抑制蛋白合成和增加蛋白清除。
Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multi-functionality poses a great challenge for understanding the mechanisms by which mitochondrial dysfunction causes specific pathologies. Among the leading mitochondrial mediators of cell death are energy depletion, free radical production, defects in iron–sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signalling molecules, and altered stress signalling. Here we identify a new pathway of mitochondria-mediated cell death in yeast. This pathway was named mitochondrial precursor over-accumulation stress (mPOS), and is characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage that is not limited to the core machineries of protein import. We also discover a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, messenger RNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were upregulated, including Gis2 and Nog2, which promote cap-independent translation and inhibit the nuclear export of the 60S ribosomal subunit, respectively. Gis2 and Nog2 upregulation promotes cell survival, which may be part of a feedback loop that attenuates mPOS. Our data indicate that mitochondrial dysfunction contributes directly to cytosolic proteostatic stress, and provide an explanation for the association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (for example, spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.
来源： Nature 浏览次数：2