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

TitleMitochondria-derived reactive oxygen species mediate caspase-dependent and -independent neuronal deaths.
Publication TypeJournal Article
Year of Publication2014
AuthorsMcManus, MJ, Murphy, MP, Franklin, JL
JournalMol Cell Neurosci
Volume63
Pagination13-23
Date Published2014 Nov
ISSN1095-9327
KeywordsAnimals, Antioxidants, Apoptosis, Caspases, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Mitochondria, Nerve Growth Factors, Neurons, Organophosphorus Compounds, Reactive Oxygen Species, Ubiquinone
Abstract

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.

DOI10.1016/j.mcn.2014.09.002
Alternate JournalMol. Cell. Neurosci.
Citation Key10.1016/j.mcn.2014.09.002
PubMed ID25239010
PubMed Central IDPMC4250393
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R01 NS037110 / NS / NINDS NIH HHS / United States
R01NS37110 / NS / NINDS NIH HHS / United States