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Sirtuin 3, a New Target of PGC-1a, Plays an Important Role in the Suppression of ROS and Mitochondrial

By Xingxing Kong, Rui Wang, Yuan Xue, Xiaojun Liu, Huabing Zhang, Yong Chen, Fude Fang and Yongsheng Chang

Abstract

Background: Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1a induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood. Results: Here we show that PGC-1a strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1a led to decreased Sirt3 gene expression. PGC-1a activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (2407/2399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRa bound to the identified ERRE and PGC-1a co-localized with ERRa in the mSirt3 promoter. Knockdown of ERRa reduced the induction of Sirt3 by PGC-1a in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1a-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1a in C 2C 12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1a on cellular ROS production. Finally, SIRT

Year: 2013
OAI identifier: oai:CiteSeerX.psu:10.1.1.353.5457
Provided by: CiteSeerX
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