Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Mol Cell. 2010 Feb 26;37(4):529-40. doi: 10.1016/j.molcel.2010.01.015.
Genetic analyses previously implicated the matrix-localized protease ClpP in signaling the stress of protein misfolding in the mitochondrial matrix to activate nuclear-encoded mitochondrial chaperone genes in C. elegans (UPR(mt)). Here, we report that haf-1, a gene encoding a mitochondria-localized ATP-binding cassette protein, is required for signaling within the UPR(mt) and for coping with misfolded protein stress. Peptide efflux from isolated mitochondria was ATP dependent and required HAF-1 and the protease ClpP. Defective UPR(mt) signaling in the haf-1-deleted worms was associated with failure of the bZIP protein, ZC376.7, to localize to nuclei in worms with perturbed mitochondrial protein folding, whereas zc376.7(RNAi) strongly inhibited the UPR(mt). These observations suggest a simple model whereby perturbation of the protein-folding environment in the mitochondrial matrix promotes ClpP-mediated generation of peptides whose haf-1-dependent export from the matrix contributes to UPR(mt) signaling across the mitochondrial inner membrane.
先前的遗传分析表明，位于基质中的蛋白酶 ClpP 参与了将线粒体基质中错误折叠蛋白质的应激信号传递给线虫（UPR(mt)）中核编码的线粒体伴侣基因。在这里，我们报告 haf-1，一个编码线粒体定位的 ATP 结合盒蛋白的基因，是 UPR(mt) 信号传递所必需的，并且对于应对错误折叠蛋白应激也是必需的。从分离的线粒体中排出的肽是 ATP 依赖性的，需要 HAF-1 和蛋白酶 ClpP。在 haf-1 缺失的线虫中，UPR(mt) 信号传递的缺陷与 bZIP 蛋白 ZC376.7 在扰乱线粒体蛋白折叠的线虫中不能定位于核内有关，而 zc376.7(RNAi) 强烈抑制了 UPR(mt)。这些观察结果表明了一个简单的模型，即线粒体基质中蛋白质折叠环境的扰动促进了 ClpP 介导的肽的产生，这些肽的 haf-1 依赖性从基质中的输出有助于线粒体内膜的 UPR(mt) 信号传递。
