Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany.
Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
Nat Cell Biol. 2019 Apr;21(4):442-451. doi: 10.1038/s41556-019-0294-5. Epub 2019 Mar 18.
The cytosolic accumulation of mitochondrial precursors is hazardous to cellular fitness and is associated with a number of diseases. However, it is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive. Here, we show that cells rapidly launch a global transcriptional programme to restore cellular proteostasis after induction of a 'clogger' protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodelling is a combination of a 'wideband' core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the oxidative phosphorylation components, mediated by an inactivation of the HAP complex.
线粒体前体在细胞质中的积累对细胞适应性有危害，并与许多疾病有关。然而，在生理条件下不会发生这种情况。最近发现了一些允许细胞避免线粒体前体在细胞质中积累的单个机制，但它们的相互作用和调节仍然难以捉摸。在这里，我们表明，在诱导一种“堵塞物”蛋白（该蛋白减少可用的线粒体导入位点的数量）后，细胞会迅速启动一个全局转录程序，以恢复细胞的蛋白质稳态。细胞上调细胞质中的蛋白质折叠和蛋白酶系统，并下调细胞质翻译机制和许多线粒体代谢酶，大概是为了减轻过度紧张的线粒体导入系统的工作量。我们表明，这种转录重塑是由转录因子 Hsf1 和 Rpn4 调节的“宽带”核心反应和由 HAP 复合物失活介导的独特的线粒体蛋白诱导的氧化磷酸化成分的下调的组合。
