Oxidative Stress Regulating ROS Metabolism

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1), a transcriptional coactivator implicated in transducing physiological stimuli into metabolic programs, stimulates mitochondrial biogenesis and mitochondrial respiration, which generates reactive oxygen species (ROS). St-Pierre et al. exposed 10T1/2 cells to hydrogen peroxide (H₂O₂) and found that PGC-1 expression was increased along with that of mRNAs encoding ROS-detoxifying enzymes and mitochondrial uncouplers (activity of which limits ROS production). RNAi directed against PGC-1 decreased basal and H₂O₂-induced expression of PGC-1 and various components of the ROS defense system. Expression of superoxide dismutase 1 and 2 and catalase was reduced in the hearts and brains of PGC-1-null mice compared with wild-type mice. Moreover, fibroblasts derived from PGC-1-null mice had increased ROS compared with fibroblasts from wild-type mice--a decrease in H₂O₂-dependent induction of components of the ROS defense system--and were more vulnerable to H₂O₂. Experiments involving mutation of the cAMP response element (CRE), a CRE-binding protein (CREB) dominant-negative mutant, immunoblot analysis, and chromatin immunoprecipitation implicated CREB in the transcriptional activation of PGC-1 in response to oxidative stress. PGC-1-null mice showed increased neurodegeneration in the substantia nigra in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compared with wild-type mice and increased hippocampal neurodegeneration in response to kainic acid. Cultured striatal cells infected with PGC-1 adenovirus showed increased expression of PGC-1 and mRNA encoding ROS-detoxifying enzymes and increased survival when treated with paraquat or H₂O₂. Thus, the authors conclude that PGC-1 plays a critical role in regulating ROS metabolism and may present a target for therapeutic manipulation in neurodegenerative diseases associated with disordered ROS metabolism.

J. St-Pierre, S. Drori, M. Uldry, J. M. Silvaggi, J. Rhee, S. Jäger, C. Handschin, K. Zheng, J. Lin, W. Yang, D. K. Simon, R. Bachoo, B. M. Spiegelman, Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397-408 (2006). [Online Journal]