Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription
Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription
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DOI：
10.1073/pnas.0408487101
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发表时间：
2005-01-04
影响因子：
11.1
通讯作者：
Johnson, JA
中科院分区：
文献类型：
--
作者：
Calkins, MJ;Jakel, RJ;Johnson, JA
复合物II抑制剂3-硝基丙酸（3 NP）和丙二酸盐引起纹状体损伤，使人联想到亨廷顿氏病，并且已经显示在其发病机制中涉及氧化应激。由于核因子红细胞2相关因子2（Nrf 2）依赖的转录激活的抗氧化反应元件的装置是已知的协调上调参与对抗氧化应激的细胞保护基因，我们调查的意义Nrf 2在复杂II诱导的毒性。我们发现，Nrf 2缺陷细胞和Nrf 2基因敲除小鼠显着更容易受到丙二酸和3 NP，并表现出增加的抗氧化反应元件（ARE）调节的星形胶质细胞介导的转录。此外，通过纹状体内移植Nrf 2过表达的星形胶质细胞损伤前ARE预激活赋予戏剧性的保护，对复合物11抑制。这些观察结果暗示Nrf 2作为一个重要的诱导因子，在保护复杂II的神经递质介导的神经毒性。这些数据还介绍了Nrf 2介导的ARE转录作为神经退行性疾病如亨廷顿病的预防性治疗的潜在靶点。
Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex 11 inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.