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首页> 美国卫生研究院文献>The Journal of Neuroscience >Mitochondrial Translocation of p53 Mediates Release of Cytochrome c and Hippocampal CA1 Neuronal Death after Transient Global Cerebral Ischemia in Rats
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Mitochondrial Translocation of p53 Mediates Release of Cytochrome c and Hippocampal CA1 Neuronal Death after Transient Global Cerebral Ischemia in Rats

机译：p53的线粒体易位介导大鼠短暂性全脑缺血后细胞色素c和海马CA1神经元死亡的释放

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Although p53 is a key modulator of cellular stress responses, the mechanism of p53-mediated apoptosis is ambiguous. p53 can mediate apoptosis in response to death stimuli by transcriptional activation of proapoptotic genes and transcriptional-independent mechanisms. Recent studies have shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming a inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release. However, how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischemia remains unclear. We examined the interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons in rats using a transient global cerebral ischemia (tGCI) model. Western blot analysis and immunofluorescent staining revealed mitochondrial p53 translocation after tGCI in the hippocampal CA1 neurons. Coimmunoprecipitation revealed that translocated p53 bound to Bcl-XL in the mitochondrial fraction. To examine the effect of a specific p53 inhibitor on the mitochondrial p53 pathway and apoptotic cell death after tGCI, we intravenously administered pifithrin-α (PFT). Mitochondrial p53 translocation and interaction between p53 and Bcl-XL were prevented by treatment with PFT. Moreover, cytochrome c release from mitochondria and subsequent apoptotic CA1 neuronal death were decreased with PFT treatment. These results suggest that the mitochondrial p53 pathway is one of the novel mechanisms mediating delayed death of vulnerable hippocampal CA1 neurons after tGCI.
机译：尽管p53是细胞应激反应的关键调节因子，但p53介导的凋亡机制尚不清楚。 p53可通过促凋亡基因的转录激活和转录独立机制介导对死亡刺激的凋亡。最近的研究表明，p53蛋白可以通过与保护性Bcl-2家族蛋白形成抑制复合物来直接诱导线粒体外膜通透化，从而导致细胞色素c的释放。然而，脑缺血后线粒体p53途径如何介导神经元凋亡尚不清楚。我们使用短暂性全脑缺血（tGCI）模型检查了大鼠线粒体p53途径与脆弱海马CA1神经元之间的相互作用。 Western印迹分析和免疫荧光染色显示tGCI后海马CA1神经元中的线粒体p53易位。免疫共沉淀显示易位的p53在线粒体部分与Bcl-XL结合。为了检查特定的p53抑制剂对tGCI后线粒体p53途径和凋亡细胞死亡的影响，我们静脉注射了pifithrin-α（PFT）。线粒体p53易位以及p53与Bcl-XL之间的相互作用可通过PFT治疗来预防。此外，通过PFT治疗可降低线粒体释放的细胞色素c以及随后的凋亡性CA1神经元死亡。这些结果表明线粒体p53途径是介导tGCI后脆弱海马CA1神经元延迟死亡的新机制之一。

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