线粒体应激,由于功能障碍和蛋白质紊乱,触发线粒体未折叠蛋白反应(UPRMT),激活编码伴侣和蛋白酶的基因以恢复线粒体功能。尽管ATFS-1介导秀丽隐杆线虫的线粒体应激UPRMT诱导,哺乳动物线粒体应激信号传递到细胞核的机制仍不明确。这里,我们探讨了蛋白激酶R(PKR)的作用,由双链RNA(dsRNA)激活的eIF2α激酶,在线粒体应激信号中。我们发现UPRMT不会发生在缺乏PKR的细胞中,表明了它在这个过程中的关键作用。机械上,我们观察到dsRNAs在应激条件下在线粒体内积累,以及未加工的线粒体转录本。此外,我们证明了Bax/Bak通道缺陷的小鼠胚胎成纤维细胞(MEFs)中积累的线粒体dsRNAs不会释放到细胞质中,并且不会在线粒体应激时诱导UPRMT,提示Bax/Bak通道在介导线粒体应激反应中的潜在作用。这些发现增强了我们对细胞如何维持线粒体完整性的理解,对线粒体功能障碍的反应,并通过逆行信号传递应力信号到细胞核。这些知识为与线粒体应激相关的疾病的前瞻性治疗靶标提供了有价值的见解。
Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.