Department of Neurosurgery and Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Neuropathology. 2010 Aug;30(4):401-7. doi: 10.1111/j.1440-1789.2009.01086.x. Epub 2010 Jan 19.
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.
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，目前尚无研究表明其在脑缺血中的作用。因此，本研究旨在评估强制过表达 TFAM 是否可以改善短暂性前脑缺血后神经元延迟死亡。我们建立了人 TFAM 转基因（Tg）小鼠。野生型（WT）和 TFAM-Tg 小鼠接受 20 分钟双侧颈总动脉闭塞（BCCAO）。在 20 分钟 BCCAO 后 24 小时，用细胞色素 c 免疫染色来估计其从线粒体中的释放。在 20 分钟 BCCAO 后 72 小时，进行组织学分析以评估 TFAM 过表达对神经元延迟死亡的影响。在海马 CA1 区，TFAM-Tg 小鼠中的细胞色素 c 阳性神经元数量明显少于 WT 小鼠（P = 0.005）。TFAM-Tg 小鼠海马 CA1 区存活神经元的百分比明显高于 WT 小鼠（P < 0.001），并且 TFAM-Tg 小鼠中的 TUNEL 阳性神经元数量明显少于 WT 小鼠（P < 0.001）。我们的数据强烈表明，TFAM 过表达可以减少线粒体通透性转换，并改善短暂性前脑缺血后海马中的神经元延迟死亡。
