Abstract
PPARgamma coactivator 1alpha (PGC-1alpha) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examined the effect of PGC-1alpha on the metabolism of ROS. PGC-1alpha is coinduced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1alpha is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively. Increasing PGC-1alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1alpha is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Brain / pathology
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CREB-Binding Protein / metabolism
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Catalase / metabolism
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Survival / drug effects
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Glutathione Peroxidase / metabolism
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Humans
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Hydrogen Peroxide / pharmacology
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Male
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Mice
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Mice, Knockout
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Neurodegenerative Diseases / metabolism*
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Neurodegenerative Diseases / pathology
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Neurons / drug effects
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Neurons / metabolism
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Oxidants / pharmacology
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Oxidative Stress / drug effects
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Promoter Regions, Genetic / drug effects
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Reactive Oxygen Species / metabolism*
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Stem Cells / drug effects
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Stem Cells / metabolism
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Superoxide Dismutase / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
Substances
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Oxidants
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Reactive Oxygen Species
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Trans-Activators
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Transcription Factors
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Hydrogen Peroxide
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Catalase
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Glutathione Peroxidase
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Superoxide Dismutase
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CREB-Binding Protein