Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum

• Published in: Neurochemistry international 2011-07, Vol.58 (8), p.880-887
• Main Authors: Takemoto, Kana, Miyata, Shingo, Takamura, Hironori, Katayama, Taiichi, Tohyama, Masaya
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Caspase-4; Caspase-9; Cell Death - physiology; Cell Line, Tumor; Cell Survival - physiology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - physiology; Fundamental and applied biological sciences. Psychology; GRP78/BiP; HSP90 Heat-Shock Proteins - physiology; Humans; Mitochondria; Mitochondrial Proteins - physiology; TRAP1; Unfolded Protein Response - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2011.02.015

► TRAP1 knockdown activated the ER-resident caspase-4. ► TRAP1 knockdown increased the basal level of GRP78/BiP expression. ► TRAP1 knockdown decreased the basal level of CHOP expression. ► TRAP1 might be involved in the unfolded protein response (UPR) pathways. 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.