MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype
MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype
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DOI：
10.1021/acschemneuro.7b00287
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发表时间：
2017-12-01
影响因子：
5
通讯作者：
Richardson, Jason R.
中科院分区：
文献类型：
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作者：
Geldenhuys, Werner J.;Benkovic, Stanley A.;Richardson, Jason R.
线粒体功能障碍被认为在帕金森氏病(PD)的神经退行性变中起重要作用，但其发病机制尚不清楚。在这里，我们证明了线粒体生物能量学调节的一种含铁硫蛋白MitoNEET(CISD1)的丢失会导致线粒体功能障碍以及纹状体多巴胺和酪氨酸羟基酶的丢失。从缺乏mitoNEET的小鼠分离出的线粒体功能障碍，表现为活性氧自由基(ROS)升高和产生ATP的能力降低。步态分析显示，基因敲除小鼠的步长缩短，转杆表现下降，这与纹状体多巴胺的丢失一致。综上所述，这些数据表明mitoNEET KO小鼠表现出帕金森病早期神经变性的许多特征，并可能提供一个新的药物发现平台来评估用于增强神经退行性疾病中线粒体功能的化合物。
Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest that mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders.