Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Cell Sci. 2011 May 1;124(Pt 9):1396-402. doi: 10.1242/jcs.078220. Epub 2011 Apr 12.
Unfolded protein responses (UPRs) of the endoplasmic reticulum and mitochondrial matrix have been described. Here, we show that the accumulation of proteins in the inter-membrane space (IMS) of mitochondria in the breast cancer cell line MCF-7 activates a distinct UPR. Upon IMS stress, overproduction of reactive oxygen species (ROS) and phosphorylation of AKT triggers estrogen receptor (ER) activity, which further upregulates the transcription of the mitochondrial regulator NRF1 and the IMS protease OMI (officially known as HTRA2). Moreover, we demonstrate that the IMS stress-induced UPR culminates in increased proteasome activity. Given our previous report on a proteasome- and OMI-dependent checkpoint that limits the import of IMS proteins, the findings presented in this study suggest that this newly discovered UPR acts as a cytoprotective response to overcome IMS stress.
内质网和线粒体基质的未折叠蛋白反应（UPR）已被描述。在这里，我们表明乳腺癌细胞系 MCF-7 中线粒体膜间空间（IMS）中蛋白质的积累会激活独特的 UPR。在 IMS 应激下，活性氧（ROS）的过度产生和 AKT 的磷酸化触发雌激素受体（ER）活性，这进一步上调了线粒体调节剂 NRF1 和 IMS 蛋白酶 OMI（正式名称为 HTRA2）的转录。此外，我们证明 IMS 应激诱导的 UPR 最终导致蛋白酶体活性增加。鉴于我们之前关于限制 IMS 蛋白导入的蛋白酶体和 OMI 依赖性检查点的报告，本研究中的发现表明，这种新发现的 UPR 是一种细胞保护反应，可以克服 IMS 应激。
