Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities.
Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities.
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DOI：
10.1523/jneurosci.2849-11.2012
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发表时间：
2012-01-11
期刊：
影响因子：
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通讯作者：
Iadecola C
中科院分区：
文献类型：
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作者：
Zhou P;Qian L;D'Aurelio M;Cho S;Wang G;Manfredi G;Pickel V;Iadecola C
禁止蛋白是一种重要的线粒体蛋白，在许多细胞类型中涉及多种功能，但其在神经元中的作用尚不清楚。在电刺激小脑顶状核诱导缺血耐受的大鼠脑蛋白质组学筛选中，我们发现禁止素在线粒体中上调。这一观察结果促使我们研究禁止素在神经元死亡和存活中的作用。我们发现，在体内短暂缺血引起的缺血耐受性中，或在神经元培养中氧葡萄糖剥夺诱导的缺血耐受性中，prohibition也上调。细胞分离和电镜免疫标记研究表明，禁止素定位于神经元线粒体。在神经元培养物或海马切片中，禁止素的上调具有明显的神经保护作用，而禁止素基因沉默会增加神经元的易感性，这种影响与线粒体膜电位的丧失和线粒体活性氧的产生增加有关。禁止素上调与暴露于复合物I抑制剂鱼藤酮的线粒体中活性氧的产生减少有关。此外，禁止素保护复合物I活性免受鱼藤酮的抑制作用。这些观察结果，共同建立了禁止蛋白作为内源性神经保护蛋白参与缺血耐受。禁止素通过减少线粒体自由基的产生对神经元产生有益作用。复合物I活性的数据表明，禁止素可能稳定复合物I的功能。禁止素的保护作用在线粒体功能障碍和氧化应激相关的神经系统疾病中具有潜在的翻译相关性。
Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene-silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress.