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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells
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Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells

机译：mitofusin 2的损失与β-淀粉样蛋白介导的线粒体片段化和Cdk5诱导的神经元细胞氧化应激有关

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摘要

Mitochondrial dysfunction is implicated in age-related degenerative disorders such as Alzheimer's disease (AD). Maintenance of mitochondrial dynamics is essential for regulating mitochondrial function. Ab oligomers (A beta Os), the typical cause of AD, lead to mitochondrial dysfunction and neuronal loss. A beta Os have been shown to induce mitochondrial fragmentation, and their inhibition suppresses mitochondrial dysfunction and neuronal cell death. Oxidative stress is one of the earliest hallmarks of AD. Cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by disrupting the antioxidant system, including Prx2. Cdk5 is also regarded as a modulator of mitochondrial fission; however, a precise mechanistic link between Cdk5 and mitochondrial dynamics is lacking. We estimated mitochondrial morphology and alterations in mitochondrial morphology-related proteins in Neuro-2a (N2a) cells stably expressing the Swedish mutation of amyloid precursor protein (APP), which is known to increase A beta O production. We demonstrated that mitochondrial fragmentation by A beta Os accompanies reduced mitofusin 1 and 2 (Mfn1/2) levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2-related oxidative stress, has been shown to regulate Mfn1 and Mfn2 levels. Furthermore, Mfn2, but not Mfn1, over-expression significantly inhibits the A beta O-mediated cell death pathway. Therefore, these results indicate that A beta O-mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5-induced Prx2 phosphorylation.
机译：线粒体功能障碍与年龄相关的变性疾病有关，例如阿尔茨海默氏病（AD）。维持线粒体动力学对于调节线粒体功能至关重要。 Ab低聚物（A beta Os）是AD的典型病因，可导致线粒体功能障碍和神经元丢失。已显示βOs诱导线粒体片段化，其抑制作用抑制线粒体功能障碍和神经元细胞死亡。氧化应激是AD的最早标志之一。细胞周期蛋白依赖性激酶5（Cdk5）可能通过破坏抗氧化剂系统（包括Prx2）引起氧化应激。 Cdk5也被认为是线粒体裂变的调节剂。然而，Cdk5与线粒体动力学之间缺乏精确的机械联系。我们估计线粒体形态和在Neuro-2a（N2a）细胞中稳定表达淀粉样前体蛋白（APP）瑞典突变的线粒体形态相关蛋白的变化，已知这会增加A beta O的产生。我们证明，由A beta Os引起的线粒体片段化会降低线粒体蛋白1和2（Mfn1 / 2）的水平。有趣的是，Cdk5途径（包括与Prx2相关的氧化应激的磷酸化作用）已被证明可调节Mfn1和Mfn2的水平。此外，Mfn2，但不是Mfn1，过度表达显着抑制A beta O介导的细胞死亡途径。因此，这些结果表明，βO介导的氧化应激通过激活Cdk5诱导的Prx2磷酸化，通过降低Mfn2表达来触发线粒体片段化。

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