Regulating ROS Metabolism

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Science's STKE  24 Oct 2006:
Vol. 2006, Issue 358, pp. tw364
DOI: 10.1126/stke.3582006tw364

Peroxisome proliferator-activatedreceptor γ (PPARγ) coactivator 1α (PGC-1α), 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-1α 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-1α decreased basal and H2O2-induced expression of PGC-1α 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-1α-null mice compared with wild-type mice. Moreover, fibroblasts derived from PGC-1α-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-1α in response to oxidative stress. PGC-1α-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-1α adenovirus showed increased expression of PGC-1α and mRNA encoding ROS-detoxifying enzymes and increased survival when treated with paraquat or H2O2. Thus, the authors conclude that PGC-1α 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]

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