Transcription factor NF-kappa B represses ANT1 transcription and leads to mitochondrial dysfunctions.
Transcription factor NF-kappa B represses ANT1 transcription and leads to mitochondrial dysfunctions.
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转录因子 NF-kappa B 抑制 ANT1 转录并导致线粒体功能障碍
DOI：
10.1038/srep44708
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发表时间：
2017-03-20
影响因子：
4.6
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Zhang C;Jiang H;Wang P;Liu H;Sun X
线粒体是参与细胞存活与死亡的细胞内细胞器，线粒体功能障碍与神经退行性疾病相关。作为线粒体内膜中含量最为丰富的蛋白质，腺嘌呤核苷酸转位酶1（ANT1）在线粒体功能中发挥着关键作用，包括线粒体中三磷酸腺苷/二磷酸腺苷（ATP/ADP）的交换、基础质子渗漏以及线粒体通透性转换孔（mPTP）。在此，我们发现ANT1的转录受转录因子核因子κB（NF-κB）调控。NF-κB与ANT1启动子中位于+1至+20碱基对以及+41至+61碱基对处的两个NF-κB反应元件（NREs）相结合。一种NF-κB信号刺激物——肿瘤坏死因子α（TNFα），可抑制ANT1的mRNA和蛋白质表达。TNFα对NF-κB的激活会损害线粒体中ATP/ADP的交换并减少ATP生成。在T98G人胶质母细胞瘤细胞和大鼠皮质神经元中，TNFα激活NF-κB会减少钙诱导的mPTP开放，提升线粒体膜电位并增加活性氧（ROS）的生成。这些结果表明，NF-κB信号通路可能抑制ANT1基因转录并损害线粒体功能。
Mitochondria are intracellular organelles involved in cell survival and death, and dysfunctions of mitochondria are related to neurodegenerative diseases. As the most abundant protein in the mitochondrial inner membrane, adenine nucleotide translocator 1 (ANT1) plays a critical role in mitochondrial function, including the exchange of adenosine triphosphate/adenosine diphosphate (ATP/ADP) in mitochondria, basal proton leak and mitochondrial permeability transition pore (mPTP). Here, we show that ANT1 transcription is regulated by transcription factor NF-kappa B (NF-κB). NF-κB is bound to two NF-κB responsive elements (NREs) located at +1 to +20 bp and +41 to +61 bp in the ANT1 promoter. An NF-κB signalling stimulator, tumour necrosis factor alpha (TNFα), suppresses ANT1 mRNA and protein expression. Activation of NF-κB by TNFα impairs ATP/ADP exchange and decreases ATP production in mitochondria. Activation of NF-κB by TNFα decreases calcium induced mPTP opening, elevates mitochondrial potential and increases reactive oxygen species (ROS) production in both T98G human glioblastoma cells and rat cortical neurons. These results demonstrate that NF-κB signalling may repress ANT1 gene transcription and impair mitochondrial functions.