The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells
The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells
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DOI：
10.1016/j.neuint.2011.06.001
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发表时间：
2011-08-01
影响因子：
4.2
通讯作者：
Kotler, Monica L.
中科院分区：
文献类型：
--
作者：
Alaimo, Agustina;Gorojod, Roxana M.;Kotler, Monica L.
锰是一种已知的微量元素，对维持许多生化和细胞反应的正常功能和调节是必不可少的。然而，在职业或环境环境中长期暴露于高水平的锰可导致其在大脑中积累，从而导致一种称为锰中毒的退行性大脑疾病。星形胶质细胞是中枢神经系统中储存锰的主要来源，多条证据表明这些细胞在锰中毒的发生发展中起主要作用。在本研究中，我们使用大鼠星形细胞瘤C6细胞作为敏感的实验模型来研究锰神经毒性的分子机制。我们的结果表明，C6细胞经历了活性氧介导的细胞死亡，包括caspase-8和线粒体介导的响应锰的途径。暴露的细胞表现出典型的凋亡特征，如染色质凝集、细胞收缩、膜起泡、caspase-3激活和内源性底物聚(ADP-核糖)聚合酶caspase特异性切割。通过FasL、caspase-8激活和Bid裂解来评估caspase-8依赖途径的参与。线粒体途径的参与表现为线粒体膜电位的破坏，线粒体通透性转换孔的开放，细胞色素c的释放，caspase-9的激活，以及线粒体促凋亡蛋白Bcl2家族蛋白水平的增加。此外，我们的数据还首次表明线粒体碎裂在锰诱导的细胞凋亡中起着相关的作用。综上所述，这些发现有助于更深入地阐明锰诱导细胞凋亡的分子信号机制。(C)2011爱思唯尔B.V.保留所有权利。
Manganese (Mn) is a trace element known to be essential for maintaining the proper function and regulation of many biochemical and cellular reactions. However, chronic exposure to high levels of Mn in occupational or environmental settings can lead to its accumulation in the brain resulting in a degenerative brain disorder referred to as Manganism. Astrocytes are the main Mn store in the central nervous system and several lines of evidence implicate these cells as major players in the role of Manganism development. In the present study, we employed rat astrocytoma C6 cells as a sensitive experimental model for investigating molecular mechanisms involved in Mn neurotoxicity. Our results show that C6 cells undergo reactive oxygen species-mediated apoptotic cell death involving caspase-8 and mitochondrial-mediated pathways in response to Mn. Exposed cells exhibit typical apoptotic features, such as chromatin condensation, cell shrinkage, membrane blebbing, caspase-3 activation and caspase-specific cleavage of the endogenous substrate poly (ADP-ribose) polymerase. Participation of the caspase-8 dependent pathway was assessed by increased levels of FasL, caspase-8 activation and Bid cleavage. The involvement of the mitochondrial pathway was demonstrated by the disruption of the mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore, cytochrome c release, caspase-9 activation and the increased mitochondrial levels of the pro-apoptotic Bcl-2 family proteins. In addition, our data also shows for the first time that mitochondrial fragmentation plays a relevant role in Mn-induced apoptosis. Taking together, these findings contribute to a deeper elucidation of the molecular signaling mechanisms underlying Mn-induced apoptosis. (C) 2011 Elsevier B.V. All rights reserved.