Charmpilas Nikolaos, Li Qiaochu, Hoppe Thorsten
Institute for Genetics, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Biol Chem. 2025 Apr 17;406(5-7):229-236. doi: 10.1515/hsz-2025-0107. Print 2025 Aug 26.
Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPR is activated. The UPR ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPR not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPR in the invertebrate model organism and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPR in worms, flies and mice, and how UPR activation in specific tissues affects organismal metabolism and longevity.
线粒体是细胞代谢的核心枢纽，其功能障碍与多种人类疾病及衰老的发生有关。为确保在错误折叠应激下线粒体功能正常，一种名为未折叠蛋白反应（UPR）的逆行线粒体信号通路被激活。未折叠蛋白反应可确保线粒体应激信号传递至细胞核，在细胞核中诱导多种线粒体蛋白酶和伴侣蛋白的基因表达，从而形成一种保护机制以恢复线粒体蛋白质稳态和功能。重要的是，未折叠蛋白反应不仅在细胞内发挥作用，而且在物种间表现出保守的非细胞自主激活，即特定组织中的线粒体应激会引发一种影响远处器官的全身反应。在此，我们总结了无脊椎动物模式生物和哺乳动物中未折叠蛋白反应的分子基础。我们还描述了关于蠕虫、果蝇和小鼠中未折叠蛋白反应的非细胞自主激活的最新发现，以及特定组织中未折叠蛋白反应的激活如何影响机体代谢和寿命。
