Singh Shilpee, Misiak Magdalena, Beyer Cordian, Arnold Susanne
Institute for Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Glia. 2009 Nov 1;57(14):1480-91. doi: 10.1002/glia.20864.
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.
星形胶质细胞的线粒体在大脑的能量供应和神经元存活方面发挥着重要作用。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），一种线粒体毒素和亨廷顿舞蹈病（HD）的体外模型，对原代纹状体星形胶质细胞线粒体功能和活力的影响。尽管NPA是已知的琥珀酸脱氢酶不可逆抑制剂，但我们观察到NPA处理后星形胶质细胞ATP水平升高。这种效应可以通过NPA介导的细胞色素c氧化酶亚基IV同工型（COX IV）表达的改变来解释。COX同工型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，从而导致细胞死亡增加。应用针对COX IV-2的小干扰RNA揭示了COX同工型IV-2在NPA介导的氧化应激升高和坏死性细胞死亡中的因果关系。因此，我们提出了一种新的、额外的NPA诱导细胞应激和死亡的机制，该机制基于星形胶质细胞COX的结构和功能变化，并且可能间接损害神经元存活。
