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The majority of cellular superoxide is generated in the mitochondria as a by-product of normal oxidative metabolism. In the mitochondria, superoxide is detoxified by manganese superoxide dismutase (SOD2). Mice lacking SOD2 demonstrate a multifaceted neonatal lethal phenotype, including a spongiform encephalopathy that is preventable through antioxidant treatment. The molecular events behind the observed pathology in the cortex of these mice are unknown. We hypothesized that the lack of SOD2 would result in significant changes in cortical gene expression and that therapeutically beneficial antioxidant treatment would normalize the expression of some genes, providing insight into the mechanism by which mitochondrial oxidative stress results in neurodegeneration. We report the identification of gene expression profiles associated with this paradigm, which characterize the degree of response to the pharmacologic intervention. We have identified specific pathways targeted by endogenous oxidative stress, including glutathione metabolism, iron metabolism, and cell-survival pathways centering on the kinase AKT. The normalization of expression of some of these pathways by antioxidant treatment suggests approaches to treating disease in which endogenous oxidative stress plays a role.

Original publication




Journal article


Free Radic Biol Med

Publication Date





152 - 163


Animals, Antioxidants, Blotting, Western, Cell Proliferation, Cell Survival, Cluster Analysis, Computational Biology, DNA, Complementary, Free Radical Scavengers, Gene Expression Regulation, Genotype, Glutamate-Ammonia Ligase, Glutathione, Iron, Mice, Mitochondria, Neurodegenerative Diseases, Oxidative Stress, Pharmacogenetics, Phenotype, Prion Diseases, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Superoxide Dismutase