Mitochondrial calcium uniporter mediated inhibition of MPP+ neurotoxicity in PC12 Cells
Mitochondrial calcium uniporter mediated inhibition of MPP+ neurotoxicity in PC12 Cells
复制标题
线粒体钙单向转运蛋白介导的 PC12 细胞 MPP 神经毒性抑制
作者：
Huiling Wang;Menglan Zhao;Jialong Chen;Yixian Ren;Guanghai Wang;Wenjun Li;Fei Zou
帕金森病（Parkinson's disease，PD）是最严重的神经退行性疾病之一。散发性PD的病因仍不清楚。一个突出的假设是线粒体功能受损可能是缓慢和进行性神经变性的基础。线粒体钙单向转运体（MCU）是调节线粒体内Ca 2+水平的重要组分。线粒体Ca ~（2+）水平不仅通过激活Krebs循环酶来调节ATP合成速率，而且在细胞凋亡过程中传递不可逆的死亡信号。因此，本研究主要探讨MCU是否参与1-甲基-4-苯基吡啶离子（MPP+）诱导PC 12细胞凋亡。结果表明，MPP+对PC 12细胞活力有明显的抑制作用，且呈浓度和时间依赖性。随着MPP+浓度的增加，MCU的表达逐渐减少。MPP+可降低PC 12细胞线粒体跨膜电位，促进细胞凋亡。值得注意的是，预孵育与精胺，MCU特异性激动剂，或外源性表达的MCU显着减轻细胞凋亡和减少ROS的产生，这是由MPP+处理的PC 12细胞。敲低内源性MCU表达或与MCU特异性抑制剂预孵育可增强PC 12细胞凋亡和ROS。因此，MCU参与了MPP+诱导的PC 12细胞凋亡。
Parkinson’s disease (PD) is one of the most debilitating neurodegenerative disorders. The etiology of sporadic PD remains unknown. One prominent hypothesis is that impaired mitochondrial function may underlie slow and progressive neurodegeneration. Mitochondrial calcium uniporter (MCU) is a crucial component that regulates the intra-mitochondrial Ca2+ level. Mitochondria Ca2+ levels not only regulate the rate of ATP synthesis by activating Krebs cycle dehydrogenases, but also convey irreversible death signals during apoptosis. Therefore, this study focused on whether MCU involved in the apoptosis induced by 1-methyl-4-phenylpyridinium ions (MPP+) in PC12 cells. Our results showed that the viability of PC12 cells was inhibited by MPP+ in a concentration and time-dependent manner. The expression of MCU was gradually decreased with the certain concentration of MPP+. Meanwhile, MPP+ decreased the mitochondrial transmembrane potential and increased the apoptosis in PC12 cells. Notably, preincubated with Spermine, a MCU specific agonist, or exogenously expressed MCU significantly alleviated cell apoptosis and decreased the ROS production in PC12 cells which is induced by MPP+ treatment. Knockdown of endogenous MCU expression or preincubated with specific inhibitor of MCU enhance the cell apoptosis and the ROS in PC12. Thus, MCU is involved in the apoptosis in PC12 induced by MPP+.