Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Neurochem Int. 2011 Jul;58(8):880-7. doi: 10.1016/j.neuint.2011.02.015. Epub 2011 Feb 19.
Stress in mitochondria or the endoplasmic reticulum (ER) independently causes cell death. Recently, it was reported that ER stress causes mitochondrial dysfunction via p53-upregulated modulator of apoptosis (PUMA). However, little is known regarding the mitochondria molecules that mediate ER dysfunction. The present study revealed that tumor necrosis factor receptor-associated protein 1 (TRAP1), which localizes in the mitochondria, is associated with the unfolded protein response (UPR) in the ER. TRAP1 knockdown activated the ER-resident caspase-4, which is activated by ER stress, to induce cell death in humans. However, TRAP1 knockdown cells did not show a significant increase in the level of cell death at least within 24 h after early phase of ER stress in comparison with that of the control cells. This finding could be attributed to a number of reasons. TRAP1 knockdown failed to activate caspase-9, which is activated by activated caspase-4. In addition, TRAP1 knockdown increased the basal level of GRP78/BiP expression, which protects cells, and decreased the basal level of C/EBP homologous protein (CHOP) expression, which induces cell death, even under ER stress. Thus, the present study revealed that mitochondria could be a potential regulator of the UPR in the ER through mitochondrial TRAP1.
线粒体或内质网（ER）中的应激可独立引发细胞死亡。最近有报道称，内质网应激通过 p53 上调凋亡调节因子（PUMA）导致线粒体功能障碍。然而，对于介导内质网功能障碍的线粒体分子知之甚少。本研究表明，定位于线粒体的肿瘤坏死因子受体相关蛋白 1（TRAP1）与内质网中的未折叠蛋白反应（UPR）有关。TRAP1 敲低激活了内质网驻留的半胱天冬酶-4，内质网应激会激活半胱天冬酶-4，从而诱导人类细胞死亡。然而，与对照细胞相比，TRAP1 敲低细胞在 ER 应激的早期阶段后至少 24 小时内，细胞死亡水平没有显著增加。这一发现可能有几个原因。TRAP1 敲低未能激活由激活的半胱天冬酶-4激活的半胱天冬酶-9。此外，TRAP1 敲低增加了 GRP78/BiP 表达的基础水平，GRP78/BiP 表达可保护细胞，同时降低了 C/EBP 同源蛋白（CHOP）表达的基础水平，CHOP 表达诱导细胞死亡，即使在 ER 应激下也是如此。因此，本研究表明，线粒体通过线粒体 TRAP1 可能成为内质网 UPR 的潜在调节剂。
