Transcriptional repression of mitochondrial function in aging: a novel role for the silencing mediator of retinoid and thyroid hormone receptors co-repressor.
CONCLUSIONS
Mitochondrial function plays an important role in metabolic homeostasis and has been implicated in aging. Although there is still ongoing debate regarding whether mitochondrion-derived oxidative stress is causative to the aging process, interventions that increase oxidative metabolism and antioxidant pathways in animal models protect against age-related deterioration, such as metabolic diseases and neurodegenerative disorders.


BACKGROUND
One of the well-characterized transcriptional networks known to improve mitochondrial activity is mediated by transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), which is activated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), two of the major energy sensing molecules that are responsible for the longevity effect of caloric restriction in certain model systems. PGC-1α co-activates several nuclear receptors, notably members of the peroxisome proliferator-activated receptor (PPAR) family, which are key regulators of mitochondrial oxidative metabolism.


RESULTS
Although the AMPK/SIRT1-PGC-1α-PPAR axis plays a prominent role in activating mitochondrial functions, their activities are down-regulated in older animals, suggesting the involvement of dominant negative regulatory mechanisms in the process of aging.


CONCLUSIONS
In this review, we will discuss the role of a transcriptional co-repressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), whose activity and expression are increased with age, as a negative regulator of mitochondrial function that promotes aging and age-related metabolic diseases.
Division of Biological Sciences, Department of Genetics and Complex Diseases, Harvard University School of Public Health, Boston, Massachusetts, USA.
Sihao
S
Liu
Shannon M
SM
Reilly
Chih-Hao
CH
Lee
D000375:Aging; D000818:Animals; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D056985:Nuclear Receptor Co-Repressor 2