Juszkiewicz Szymon, Peak-Chew Sew-Yeu, Hegde Ramanujan S
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
Current address: Genentech, South San Francisco, CA 94080.
Mol Biol Cell. 2025 Apr 1;36(4):ar39. doi: 10.1091/mbc.E25-01-0035. Epub 2025 Jan 29.
Nearly all mitochondrial proteins are imported into mitochondria from the cytosol. How nascent mitochondrial precursors acquire and sustain import competence in the cytosol under normal and stress conditions is incompletely understood. Here, we show that under normal conditions, the Hsc70 and Hsp90 systems interact with and redundantly minimize precursor degradation. During acute import stress, Hsp90 buffers precursor degradation, preserving proteins in an import-competent state until stress resolution. Unexpectedly, buffering by Hsp90 relies critically on a mitochondrial targeting signal (MTS), the absence of which greatly decreases precursor-Hsp90 interaction. Site-specific photo-cross-linking and biochemical reconstitution showed how the MTS directly engages co-chaperones of Hsc70 (St13 and Stip1) and Hsp90 (p23 and Cdc37) to facilitate chaperone retention on the mature domain. Thus, the MTS has a previously unappreciated role in regulating chaperone dynamics on mitochondrial precursors to buffer their degradation and maintain import competence, functions that may facilitate restoration of mitochondrial homeostasis after acute import stress.
几乎所有线粒体蛋白都是从细胞质溶胶导入线粒体的。在正常和应激条件下，新生线粒体前体如何在细胞质溶胶中获得并维持导入能力，目前尚不完全清楚。在这里，我们表明，在正常条件下，Hsc70和Hsp90系统相互作用，并冗余性地使前体降解最小化。在急性导入应激期间，Hsp90缓冲前体降解，将蛋白质保持在导入能力状态，直至应激解除。出乎意料的是，Hsp90的缓冲作用严重依赖线粒体靶向信号（MTS），缺乏该信号会大大降低前体与Hsp90的相互作用。位点特异性光交联和生化重组表明，MTS如何直接与Hsc70（St13和Stip1）和Hsp90（p23和Cdc37）的共伴侣结合，以促进伴侣蛋白保留在成熟结构域上。因此，MTS在调节线粒体前体上的伴侣蛋白动态以缓冲其降解并维持导入能力方面具有以前未被认识到的作用，这些功能可能有助于急性导入应激后恢复线粒体稳态。
