Su Kimmy, Bourdette Dennis, Forte Michael
Vollum Institute, Oregon Health and Science University Portland, OR, USA.
Front Physiol. 2012 Jul 20;3:285. doi: 10.3389/fphys.2012.00285. eCollection 2012.
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 (H(2)O(2)) 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.
线粒体对于神经元的生存能力和功能至关重要，因为它们在三磷酸腺苷（ATP）生成、细胞内钙调节以及凋亡途径激活中发挥作用。因此，线粒体功能障碍已在多种神经退行性疾病中被指出，包括阿尔茨海默病（AD）、亨廷顿舞蹈病、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，其中病理性开放会导致线粒体肿胀、破裂、细胞色素c释放以及神经元死亡。活性氧（ROS）作为PTP开放的诱导剂，在许多此类神经退行性疾病的进展中起着重要作用。在这种情况下，最近研究表明，一种靶向线粒体的氧化还原酶p66ShcA（p66）失活可防止在MS小鼠模型实验性自身免疫性脑脊髓炎（EAE）中导致轴突切断的神经元细胞死亡。为了进一步表征缺乏p66的神经元的反应，我们评估了它们对涉及神经退行性途径的应激源治疗的反应。具体而言，用过氧化氢（H₂O₂）和一氧化氮（NO）处理p66基因敲除（p66-KO）和野生型（WT）神经元，并评估细胞活力以及线粒体特性的变化，包括形态和ROS生成。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具有更高的存活率，并且产生的ROS更少。相应地，p66-KO神经元中的线粒体对这些挑战的形态变化较小。总体而言，这些发现突出了开发针对神经退行性疾病的线粒体靶向治疗方法的重要性，并强调p66、线粒体ROS和PTP是维持线粒体和神经元完整性的关键靶点。
