Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage
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DOI：
10.1073/pnas.0508215102
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发表时间：
2005-12-27
影响因子：
11.1
通讯作者：
Vila, M
中科院分区：
文献类型：
--
作者：
Perier, C;Tieu, K;Vila, M
线粒体复合物I的功能障碍是人类神经退行性疾病如Leber遗传性视神经病变和帕金森病的特征。这种线粒体缺陷与体内细胞凋亡依赖性途径的募集有关。然而，在分离的脑线粒体中，由药理学或遗传手段引起的复合物I功能障碍未能直接激活该细胞死亡途径。相反，赤字的复合物I刺激线粒体内的氧化应激，这反过来又增加了线粒体膜间隙内的细胞色素c的可释放的可溶性池。在通过细胞死亡激动剂Bax的线粒体透化后，更多的细胞色素c从具有受损的复合物I活性的脑线粒体释放到胞质溶胶中。鉴于这些结果，我们提出了一个模型，其中复合物I的缺陷降低了Bax激活神经元依赖性凋亡的阈值，从而使受损的神经元更容易退化。这种分子情景可能对这些不治之症的有效神经保护疗法的发展产生深远的影响。
Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.