Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators

PPAR gamma coactivator 1 alpha (PGC-1 alpha) 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-1 alpha on the metabolism of ROS. PGC-1 alpha 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-1 alpha is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1 alpha 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-1 alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1 alpha is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.