title: Mitochondria-derived reactive oxygen species mediate caspase-dependent and -independent neuronal deaths.
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.
authors.affiliation: 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. Electronic address: megangm@gmail.com.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McManus
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. Electronic address: michael.murphy@mrc-mbu.cam.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 357 Wilson Pharmacy, Athens, GA 30602, USA. Electronic address: jfrankli@rx.uga.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Franklin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000172:deficiency; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D009414:Nerve Growth Factors; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone; D020169:Caspases
keywords: Apoptosis; Caspase; Cytochrome c; MitoQ; Mitochondria; ROS