Corepressor Modulation of Oxidative Metabolism and Aging

The transcriptional corepressor SMRT utilizes two major receptor interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We report here a mouse model with RID1 knockin mutations (SMRTmRID1), which shifts SMRT repression to RID2-associated NRs, notably peroxisome proliferator-activated receptors (PPARs). SMRT mRID1 mice exhibit reduced mitochondrial function and antioxidant gene expression, leading to premature aging and related metabolic diseases. These defects are mediated partly by suppressed PPAR activity and the increased susceptibility to oxidative damage in SMRTmRID1 cells could be rescued by PPAR activation or antioxidant treatment. In concert, SMRT occupancy on PPAR target gene promoter is increased with age and its overexpression inhibits the antioxidant defense pathway and reduces stress resistance. These data uncover a role for SMRT in mitochondrial oxidative metabolism, metabolic disease and the aging process [1].