Mitochondria-derived reactive oxygen species mediate caspase-dependent and-independent neuronal deaths

作者：McManus Meagan J; Murphy Michael P; Franklin James L^*

来源：Molecular and Cellular Neuroscience, 2014, 63: 13-23.

DOI：10.1016/j.mcn2014.09.002

• MitoQ
• Apoptosis
• Caspase
• ROS
• Mitochondria
• Cytochrome c

Mitochondria( 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 MitoQ(10) and MitoE(2) 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 MitoQ(10) to scavenge mitachondrial superoxide O-2(.-). MitoQ(10) 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.

• 出版日期2014-11