McManus Meagan J, Murphy Michael P, Franklin James L
Center of Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Blvd, Room 6100, Philadelphia, PA 19104, USA.
MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
Mol Cell Neurosci. 2014 Nov;63:13-23. doi: 10.1016/j.mcn.2014.09.002. Epub 2014 Sep 16.
Mitochondrial dysfunction and oxidative stress are implicated in many neurodegenerative diseases. Mitochondria-targeted drugs that effectively decrease oxidative stress, protect mitochondrial energetics, and prevent neuronal loss may therefore lend therapeutic benefit to these currently incurable diseases. To investigate the efficacy of such drugs, we examined the effects of mitochondria-targeted antioxidants MitoQ10 and MitoE2 on neuronal death induced by neurotrophin deficiency. Our results indicate that MitoQ10 blocked apoptosis by preventing increased mitochondria-derived reactive oxygen species (ROS) and subsequent cytochrome c release, caspase activation, and mitochondrial damage in nerve growth factor (NGF)-deprived sympathetic neurons, while MitoE2 was largely ineffective. In this paradigm, the most proximal point of divergence was the ability of MitoQ10 to scavenge mitochondrial superoxide (O2(-)). MitoQ10 also prevented caspase-independent neuronal death in these cells demonstrating that the mitochondrial redox state significantly influences both apoptotic and nonapoptotic pathways leading to neuronal death. We suggest that mitochondria-targeted antioxidants may provide tools for delineating the role and significance of mitochondrial ROS in neuronal death and provide a new therapeutic approach for neurodegenerative conditions involving trophic factor deficits and multiple modes of cell death.
线粒体功能障碍和氧化应激与许多神经退行性疾病有关。因此，能有效降低氧化应激、保护线粒体能量代谢并防止神经元丢失的线粒体靶向药物可能会为这些目前无法治愈的疾病带来治疗益处。为了研究此类药物的疗效，我们检测了线粒体靶向抗氧化剂MitoQ10和MitoE2对神经营养因子缺乏诱导的神经元死亡的影响。我们的结果表明，MitoQ10通过防止线粒体衍生的活性氧（ROS）增加以及随后的细胞色素c释放、半胱天冬酶激活和线粒体损伤，从而阻断了神经生长因子（NGF）剥夺的交感神经元中的细胞凋亡，而MitoE2在很大程度上无效。在这种模式下，最主要的差异点在于MitoQ10清除线粒体超氧化物（O2(-)）的能力。MitoQ10还能防止这些细胞中不依赖半胱天冬酶的神经元死亡，这表明线粒体氧化还原状态显著影响导致神经元死亡的凋亡和非凋亡途径。我们认为，线粒体靶向抗氧化剂可能为阐明线粒体ROS在神经元死亡中的作用和意义提供工具，并为涉及营养因子缺乏和多种细胞死亡模式的神经退行性疾病提供一种新的治疗方法。
