Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration

SummaryThe 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 find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRTmRID1) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRTmRID1 cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (41 K)Download as PowerPoint slideHighlights► SMRT expression is upregulated in major metabolic tissues in older animals ► SMRT occupancy on PPAR target gene promoters is increased with age ► SMRT repression of PPAR-regulated mitochondrial function accelerates aging ► Human SMRT gene SNPs nominally associate with type 2 diabetes and adiponectin levels