title: Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice.
abstract: Oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative disorders such as Parkinson's and Alzheimer's disease. However, it is not yet understood how endogenous mitochondrial oxidative stress may result in mitochondrial dysfunction. Most prior studies have tested oxidative stress paradigms in mitochondria through either chemical inhibition of specific components of the respiratory chain, or adding an exogenous insult such as hydrogen peroxide or paraquat to directly damage mitochondria. In contrast, mice that lack mitochondrial superoxide dismutase (SOD2 null mice) represent a model of endogenous oxidative stress. SOD2 null mice develop a severe neurological phenotype that includes behavioral defects, a severe spongiform encephalopathy, and a decrease in mitochondrial aconitase activity. We tested the hypothesis that specific components of the respiratory chain in the brain were differentially sensitive to mitochondrial oxidative stress, and whether such sensitivity would lead to neuronal cell death. We carried out proteomic differential display and examined the activities of respiratory chain complexes I, II, III, IV, V, and the tricarboxylic acid cycle enzymes alpha-ketoglutarate dehydrogenase and citrate synthase in SOD2 null mice in conjunction with efficacious antioxidant treatment and observed differential sensitivities of mitochondrial proteins to oxidative stress. In addition, we observed a striking pattern of neuronal cell death as a result of mitochondrial oxidative stress, and were able to significantly reduce the loss of neurons via antioxidant treatment.
authors.affiliation: Buck Institute for Age Research, Novato, California 94945, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hinerfeld
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Traini
authors.forename: Ron P
authors.initials: RP
authors.lastname: Weinberger
authors.forename: Bruce
authors.initials: B
authors.lastname: Cochran
authors.forename: Susan R
authors.initials: SR
authors.lastname: Doctrow
authors.forename: Jenny
authors.initials: J
authors.lastname: Harry
authors.forename: Simon
authors.initials: S
authors.lastname: Melov
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D040901:Proteomics / Q000379:methods*; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2