Cytochrome c Oxidase Isoform IV-2 is Involved in 3-Nitropropionic Acid-Induced Toxicity in Striatal Astrocytes
Cytochrome c Oxidase Isoform IV-2 is Involved in 3-Nitropropionic Acid-Induced Toxicity in Striatal Astrocytes
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DOI：
10.1002/glia.20864
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发表时间：
2009-11-01
期刊：
影响因子：
6.2
通讯作者：
Arnold, Susanne
中科院分区：
文献类型：
--
作者：
Singh, Shilpee;Misiak, Magdalena;Arnold, Susanne
星形胶质细胞线粒体在脑内能量供应和神经元存活中起重要作用。毒性和退行性过程在很大程度上与线粒体功能障碍有关。因此，我们研究了3-硝基丙酸（NPA），线粒体毒素和体外模型的亨廷顿病（HD），对原代纹状体星形胶质细胞的线粒体功能和活力的影响。虽然NPA被认为是琥珀酸脱氢酶的不可逆抑制剂，但我们观察到NPA处理后星形胶质细胞ATP水平增加。这种效应可以解释NPA介导的细胞色素c氧化酶亚基IV亚型（考克斯IV）表达的改变。考克斯亚型IV-2的上调导致酶活性增加，但以线粒体过氧化物产生增加为代价，导致细胞死亡增加。针对考克斯IV-2的小干扰RNA的应用揭示了考克斯亚型IV-2在NPA介导的氧化应激和坏死细胞死亡升高中的因果关系。因此，我们提出了一种新的，额外的NPA诱导的细胞应激和死亡的机制，这是基于星形胶质细胞考克斯的结构和功能的变化，并可能间接损害神经元的生存。(C)2009 Wiley-Liss，Inc.
Astrocyte mitochondria play an important role for energy supply and neuronal survival in the brain. Toxic and degenerative processes are largely associated with mitochondrial dysfunction. We, therefore, investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and in vitro model of Huntington's disease (HD), on mitochondrial function and viability of primary striatal astrocytes. Although NPA is known as an irreversible inhibitor of succinate dehydrogenase, we observed an increase of astrocyte ATP levels after NPA treatment. This effect could be explained by NPA-mediated alterations of cytochrome c oxidase subunit IV isoform (COX IV) expression. The up-regulation of COX isoform IV-2 caused an increased enzyme activity at the expense of elevated mitochondrial peroxide production causing increased cell death. The application of a small interfering RNA against COX IV-2 revealed the causal implication of COX isoform IV-2 in NPA-mediated elevation of oxidative stress and necrotic cell death. Thus, we propose a novel, additional mechanism of NPA-induced cell stress and death which is based on structural and functional changes of astrocyte COX and which could indirectly impair neuronal survival. (C) 2009 Wiley-Liss, Inc.