Zhou He-Yan, Sun Yu-Ying, Chang Ping, Huang Han-Chang
Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing, 100191, China.
Institute of Functional Factors and Brain Sciences, Beijing Union University, Beijing, 100023, China.
Neurotox Res. 2022 Apr;40(2):449-460. doi: 10.1007/s12640-022-00481-y. Epub 2022 Feb 22.
Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been suggested to relate with the pathology of Alzheimer's disease (AD). However, their cross-talk is needed to investigate further. Mitofusin-2 (Mfn2) is a member of mitochondria-associated membrane (MAM), which connects endoplasmic reticulum (ER) and mitochondria. This study investigated the protective effect of curcumin on thapsigargin (TG)-induced ERS and cell apoptosis and the role of Mfn2 on mitochondrial dysfunction. The cell viability of SH-SY5Y cells was decreased and cell damage and apoptosis were increased in a concentration-dependent manner when cells were treated with TG. TG upregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. Curcumin attenuated TG-induced damage on cell viability and apoptosis and downregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. TG caused the increases in intracellular reactive oxygen species (ROS) and in the protein levels of pSer40-Nrf2 and hemoglobin oxygenase 1 (HO-1). Curcumin decreased the TG-induced intracellular ROS but did not alter the protein levels of pSer40-Nrf2 and HO-1. TG resulted in the upregulation on Mfn2 expression and mitochondrial spare respiratory capacity but the downregulation on mitochondrial basal respiration and ATP production. Curcumin attenuated the TG-induced Mfn2 expression and mitochondrial stress. When Mfn2 was silenced by shRNA interference, curcumin failed to recovery the TG-damaged mitochondrial function. In general, the TG-induced ERS trigged mitochondrial dysfunction and cell apoptosis. Curcumin attenuates TG-induced ERS and the cell damage and apoptosis. Mfn2 is required for curcumin's protection against the TG-induced damage on mitochondrial functions.
内质网应激（ERS）和线粒体功能障碍被认为与阿尔茨海默病（AD）的病理过程有关。然而，它们之间的相互作用仍需进一步研究。线粒体融合蛋白2（Mfn2）是线粒体相关膜（MAM）的成员之一，它连接内质网（ER）和线粒体。本研究探讨了姜黄素对毒胡萝卜素（TG）诱导的ERS和细胞凋亡的保护作用以及Mfn2在线粒体功能障碍中的作用。用TG处理细胞时，SH-SY5Y细胞的活力降低，细胞损伤和凋亡呈浓度依赖性增加。TG上调了GRP78、pSer981-PERK和pSer51-eIF2α的蛋白水平。姜黄素减轻了TG诱导的细胞活力损伤和凋亡，并下调了GRP78、pSer981-PERK和pSer51-eIF2α的蛋白水平。TG导致细胞内活性氧（ROS）增加以及pSer40-Nrf2和血红素加氧酶1（HO-1）的蛋白水平升高。姜黄素降低了TG诱导的细胞内ROS，但未改变pSer40-Nrf2和HO-1的蛋白水平。TG导致Mfn2表达上调和线粒体备用呼吸能力增强，但线粒体基础呼吸和ATP生成下调。姜黄素减轻了TG诱导的Mfn2表达和线粒体应激。当通过shRNA干扰使Mfn2沉默时，姜黄素未能恢复TG损伤的线粒体功能。总体而言，TG诱导的ERS引发了线粒体功能障碍和细胞凋亡。姜黄素减轻了TG诱导的ERS以及细胞损伤和凋亡。Mfn2是姜黄素保护细胞免受TG诱导的线粒体功能损伤所必需的。
