Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke
Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke
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DOI：
10.1016/j.bbrc.2014.01.032
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发表时间：
2014-02-07
影响因子：
3.1
通讯作者：
Sun, Xiaojiang
中科院分区：
文献类型：
--
作者：
Li, Qiang;Zhang, Ting;Sun, Xiaojiang
雷帕霉素已被证明通过在脑缺血模型中激活自噬而表现出神经保护功能。然而，线粒体自噬在这一过程中的参与及其对线粒体功能保护的贡献仍然未知。本研究探讨了脑缺血后线粒体自噬的特点及雷帕霉素对线粒体功能的影响。雄性Sprague-Dawley大鼠接受短暂性大脑中动脉闭塞（tMCA 0）。神经功能缺损评分;梗死体积;线粒体自噬形态学;测定丙二醛（MDA）、三磷酸腺苷（ATP）含量及线粒体膜电位（Δ psi m）。应用透射电镜观察缺血后线粒体LC 3、Beclin-1和p62蛋白的表达变化。我们还使用3-甲基腺嘌呤（3-MA）阻断自噬体的形成，以检查雷帕霉素的线粒体保护作用和增强的线粒体自噬之间的联系。我们观察到雷帕霉素显著增强线粒体自噬，如线粒体中LC 3-II和Beclin-1表达的增加和p62易位到线粒体所证明的。与对照动物相比，雷帕霉素减少了梗死体积，改善了神经学结果并抑制了线粒体功能障碍（p < 0.05）。然而，这些保护作用被雷帕霉素后的3-甲基腺嘌呤处理逆转。目前的研究表明，雷帕霉素治疗减轻脑缺血后线粒体功能障碍，这与增强线粒体自噬有关。皇冠版权所有（C）2014由Elsevier Inc.发布。All rights reserved.
Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCA0). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Delta psi m) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarct volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p < 0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved.