Manganese induces mitochondrial dynamics impairment and apoptotic cell death: A study in human Gli36 cells
Manganese induces mitochondrial dynamics impairment and apoptotic cell death: A study in human Gli36 cells
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DOI：
10.1016/j.neulet.2013.08.061
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发表时间：
2013-10-25
影响因子：
2.5
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（Mn）是一种必需的微量元素，由于其参与许多生理过程。然而，过度暴露于这种金属会导致一种称为锰中毒的神经系统疾病，其临床表现和分子机制类似于帕金森病。几条证据表明星形胶质细胞是锰神经毒性的早期靶点，线粒体是受影响最严重的细胞器。本研究的目的是探讨锰暴露的人星形胶质细胞中可能的线粒体动力学改变。因此，我们采用表达星形胶质细胞标志物GFAP和S100 B的Gli 36细胞。我们证明，锰触发线粒体凋亡途径揭示Bax/Bcl-2比值增加，线粒体膜电位的损失和caspase-9激活。这种凋亡程序可能反过来负责caspase-3/7激活，PARP-1切割，染色质浓缩和断裂。此外，我们确定，锰诱导去调节的线粒体形成蛋白（Opa-1，Mfn-2和Drp-1）的表达水平与线粒体网络的破坏，朝着一个加剧的碎片。由于线粒体动力学在几种神经退行性疾病中发生改变，这些蛋白质可能成为锰中毒治疗中考虑的未来目标。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Manganese (Mn) is an essential trace element due to its participation in many physiological processes. However, overexposure to this metal leads to a neurological disorder known as Manganism whose clinical manifestations and molecular mechanisms resemble Parkinson's disease. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity being the mitochondria the most affected organelles. The aim of this study was to investigate the possible mitochondrial dynamics alterations in Mn-exposed human astrocytes. Therefore, we employed Gli36 cells which express the astrocytic markers GFAP and S100B. We demonstrated that Mn triggers the mitochondrial apoptotic pathway revealed by increased Bax/BcI-2 ratio, by the loss of mitochondrial membrane potential and by caspase-9 activation. This apoptotic program may be in turn responsible of caspase-3/7 activation, PARP-1 cleavage, chromatin condensation and fragmentation. In addition, we determined that Mn induces deregulation in mitochondria-shaping proteins (Opa-1, Mfn-2 and Drp-1) expression levels in parallel with the disruption of the mitochondrial network toward to an exacerbated fragmentation. Since mitochondrial dynamics is altered in several neurodegenerative diseases, these proteins could become future targets to be considered in Manganism treatment. (C) 2013 Elsevier Ireland Ltd. All rights reserved.