Human AP endonuclease/redox factor APE1/ref-1modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1
Human AP endonuclease/redox factor APE1/ref-1modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1
复制标题
人AP核酸内切酶/氧化还原因子APE1/ref-1通过调节NRF1的转录活性来调节氧化应激后的线粒体功能
DOI：
10.1016/j.freeradbiomed.2012.04.002
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发表时间：
2012-07-15
影响因子：
7.4
通讯作者：
Wang, Dong
中科院分区：
文献类型：
--
作者：
Li, Mengxia;Vascotto, Carlo;Wang, Dong
线粒体功能的维持很大程度上取决于核转录，因为大多数线粒体蛋白质由核基因组编码并转运到线粒体。核呼吸因子1（NRF 1）在调节细胞核中多种线粒体基因的表达以响应细胞氧化应激中起着至关重要的作用。然而，关于NRF 1转录活性的氧化还原调节机制知之甚少。在这项研究中，我们表明，人类脱嘌呤/脱嘧啶核酸内切酶/氧化还原因子（APE 1/Ref-1）参与线粒体功能的调节，通过调节DNA结合活性的NRF 1。我们的研究结果表明，APE 1的表达水平和氧化还原活性是必不可少的维护线粒体功能后，叔丁基过氧化氢诱导的氧化应激。在敲低APE 1或氧化还原突变后，NRF 1 DNA结合活性受损，因此，其下游基因（包括Tfam、Cox 6c和Tomm 22）的表达显著降低。NRF 1敲低阻断了APE 1过表达对线粒体功能的恢复，这进一步表明APE 1通过NRF 1依赖性途径调节线粒体功能。综上所述，我们的研究结果揭示了APE 1作为NRF 1的一种新的共激活因子，这突出了APE 1在维持线粒体功能方面的额外调节作用。(C)2012 Elsevier Inc. All rights reserved.
Maintenance of mitochondrial functionality largely depends on nuclear transcription because most mitochondrial proteins are encoded by the nuclear genome and transported to the mitochondria. Nuclear respiration factor 1 (NRF1) plays a crucial role in regulating the expression of a broad range of mitochondrial genes in the nucleus in response to cellular oxidative stress. However, little is known about the redox regulatory mechanism of the transcriptional activity of NRF1. In this study, we show that the human apurinic/apyrimidinic endonuclease/redox factor (APE1/Ref-1) is involved in mitochondrial function regulation by modulating the DNA-binding activity of NRF1. Our results show that both APE1 expression level and its redox activity are essential for maintenance of the mitochondrial function after tert-butylhydroperoxide-induced oxidative stress. Upon knocking down or redox mutation of APE1, NRF1 DNA-binding activity was impaired and, consequently, the expression of its downstream genes, including Tfam, Cox6c, and Tomm22, was significantly reduced. NRF1 knockdown blocked the restoration of mitochondrial function by APE1 overexpression, which further suggests APE1 regulates mitochondrial function through an NRF1-dependent pathway. Taken together, our results reveal APE1 as a new coactivator of NRF1, which highlights an additional regulatory role of APE1 in maintenance of mitochondrial functionality. (C) 2012 Elsevier Inc. All rights reserved.