Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges.
Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges.
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DOI：
10.3389/fphys.2012.00285
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发表时间：
2012
影响因子：
4
通讯作者：
Forte M
中科院分区：
文献类型：
--
作者：
Su K;Bourdette D;Forte M
线粒体对神经元的存活和功能是必不可少的，因为它们在ATP的产生、细胞内钙调节和凋亡通路的激活中起着重要作用。因此，线粒体功能障碍在多种神经退行性疾病中被发现，包括阿尔茨海默病(AD)、亨廷顿病、肌萎缩侧索硬化症、中风和多发性硬化症(MS)。最近的证据表明，通透性转换孔(PTP)是这些疾病中线粒体功能障碍的关键因素，在这些疾病中，病理性开放会导致线粒体肿胀、破裂、细胞色素c释放和神经元死亡。活性氧簇(ROS)是PTP开放的诱导物，与许多神经退行性疾病的进展密切相关。在这种背景下，线粒体靶向氧化还原酶p66ShcA(P66)的失活最近被证明可以防止MS小鼠模型-实验性自身免疫性脑脊髓炎(EAE)的神经细胞死亡导致轴突切断。为了进一步描述缺乏p66的神经元的反应，我们评估了它们对神经退行性变通路中涉及的应激源治疗的反应。具体地说，p66基因敲除(p66-KO)和野生型(WT)神经元被过氧化氢(H_2O_2)和一氧化氮(NO)处理，并评估细胞活力和线粒体特性的变化，包括形态和ROS产生。结果表明，与WT神经元相比，P66-KO神经元在每种应激源处理后的存活率更高，产生的ROS更少。相应地，p66-KO神经元中的线粒体对这些挑战的反应表现出减少的形态变化。总体而言，这些发现强调了开发针对神经退行性疾病的线粒体靶向疗法的重要性，并强调了p66、线粒体ROS和PTP作为维持线粒体和神经元完整性的关键靶点。
Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis (MS). Recent evidence points to the permeability transition pore (PTP) as a key player in mitochondrial dysfunction in these diseases, in which pathologic opening leads to mitochondrial swelling, rupture, release of cytochrome c, and neuronal death. Reactive oxygen species (ROS), which are inducers of PTP opening, have been prominently implicated in the progression of many of these neurodegenerative diseases. In this context, inactivation of a mitochondria-targeted redox enzyme p66ShcA (p66) has been recently shown to prevent the neuronal cell death leading to axonal severing in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). To further characterize the response of neurons lacking p66, we assessed their reaction to treatment with stressors implicated in neurodegenerative pathways. Specifically, p66-knockout (p66-KO) and wild-type (WT) neurons were treated with hydrogen peroxide (H2O2) and nitric oxide (NO), and assessed for cell viability and changes in mitochondrial properties, including morphology and ROS production. The results showed that p66-KO neurons had greater survival following treatment with each stressor and generated less ROS when compared to WT neurons. Correspondingly, mitochondria in p66-KO neurons showed diminished morphological changes in response to these challenges. Overall, these findings highlight the importance of developing mitochondria-targeted therapeutics for neurodegenerative disorders, and emphasize p66, mitochondrial ROS, and the PTP as key targets for maintaining mitochondrial and neuronal integrity.
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影响因子：
64.5
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通讯作者：
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Du Yan, Shi
影响因子：
3.3
作者：
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