Nuclear receptor corepressor SMRT regulates mitochondrial oxidative metabolism and mediates aging-related metabolic deterioration.
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 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 (SMRT(mRID1)) 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. SMRT(mRID1) 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.
Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Shannon M
SM
Reilly
Prerna
P
Bhargava
Sihao
S
Liu
Matthew R
MR
Gangl
Cem
C
Gorgun
Russell R
RR
Nofsinger
Ronald M
RM
Evans
Lu
L
Qi
Frank B
FB
Hu
Chih-Hao
CH
Lee
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D052242:Adiponectin; D056985:Nuclear Receptor Co-Repressor 2; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear