Overexpression of mitochondrial transcription factor A (TFAM) ameliorates delayed neuronal death due to transient forebrain ischemia in mice
Overexpression of mitochondrial transcription factor A (TFAM) ameliorates delayed neuronal death due to transient forebrain ischemia in mice
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DOI：
10.1111/j.1440-1789.2009.01086.x
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发表时间：
2010-08-01
期刊：
影响因子：
2.3
通讯作者：
Iwasaki, Yoshinobu
中科院分区：
文献类型：
--
作者：
Hokari, Masaaki;Kuroda, Satoshi;Iwasaki, Yoshinobu
线粒体转录因子A（TFAM）是维持线粒体DNA拷贝数的重要调节因子。然而，没有研究表明它在脑缺血中的作用。因此，本研究旨在评估TFAM的强制过表达是否改善短暂性前脑缺血后的迟发性神经元死亡。我们建立了人TFAM转基因（Tg）小鼠。对野生型（WT）和TFAM-Tg小鼠进行20分钟的双侧颈总动脉闭塞（BCCAO）。对细胞色素c进行免疫染色，以估计其释放从线粒体在24小时后20分钟BCCAO。进行组织学分析以评估TFAM过表达对BCCAO 20分钟后72小时的迟发性神经元死亡的影响。TFAM-Tg小鼠海马CA 1区细胞色素c阳性神经元的数量显著小于WT小鼠（P = 0.005）。TFAM-Tg小鼠海马CA 1区存活神经元百分比显著高于WT小鼠（P < 0.001），TUNEL阳性神经元数目显著低于WT小鼠（P < 0.001）。我们的数据有力地表明，TFAM过表达可以减少线粒体通透性转换和改善短暂前脑缺血后海马迟发性神经元死亡。
Mitochondrial transcription factor A (TFAM) is an important regulator to maintain mitochondrial DNA copy number. However, no studies have denoted its roles in cerebral ischemia. Therefore, this study was aimed to assess whether the forced overexpression of TFAM ameliorates delayed neuronal death following transient forebrain ischemia. We have established human TFAM-transgenic (Tg) mice. Wild type (WT) and TFAM-Tg mice were subjected to 20-min bilateral common carotid artery occlusion (BCCAO). Immunostaining against cytochrome c was performed to estimate its release from mitochondria at 24 h after 20-min BCCAO. Histological analysis was performed to evaluate the effect of TFAM overexpression on delayed neuronal death at 72 h after 20-min BCCAO. The number of cytochrome c-positive neurons in the hippocampal CA1 sector was significantly smaller in TFAM-Tg mice than in WT mice (P = 0.005). The percentage of viable neurons in the hippocampal CA1 sector was significantly higher in TFAM-Tg mice than in WT mice (P < 0.001), and the number of TUNEL-positive neurons was significantly smaller in TFAM-Tg mice than in WT mice (P < 0.001). Our data strongly suggest that TFAM overexpression can reduce mitochondrial permeability transition and ameliorate delayed neuronal death in the hippocampus after transient forebrain ischemia.