SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes

Abstract

SIRT3 is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene, which mediates the effect of caloric restriction on life span extension in yeast and Caenorhabditis elegans. Because adipose tissue is essential in energy homeostasis and also plays a role in life span determination, we decided to investigate the function of sirtuin members in fat. We report here that murine SIRT3 is expressed in brown adipose tissue and is localized on the mitochondria inner membrane. Caloric restriction activates SIRT3 expression in both white and brown adipose. Additionally, cold exposure up-regulates SIRT3 expression in brown fat, whereas elevated climate temperature reduces the expression. Enforced expression of SIRT3 in the HIB1B brown adipocytes enhances the expression of the uncoupling protein PGC-1␣, UCP1, and a series of mitochondria-related genes. Both ADP-ribosyltransferase and deacetylase activities of SIRT3 are required for this action. Furthermore, the SIRT3 deacetylase mutant exhibits a dominant negative effect by inhibiting UCP1 expression. This inhibitive effect can be abolished by the coexpression of PGC-1␣, indicating a major role of PGC-1␣ in the SIRT3 action. In addition, SIRT3 stimulates CREB phosphorylation, which reportedly activates PGC-1␣ promoter directly. Functionally, sustained expression of SIRT3 decreases membrane potential and reactive oxygen species production while increasing cellular respiration. Finally, SIRT3, along with genes related to mitochondrial function, is down-regulated in the brown adipose tissue of several genetically obese mice. In summary, our results demonstrate that SIRT3 activates mitochondria functions and plays an important role in adaptive thermogenesis in brown adipose.

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

“…To define the effects of SIRT3 on p53‐dependent neuronal activity, we cotransfected mito‐p53 with WT SIRT3 or ΔSIRT3 in DIV7 primary cortical neurons and determined neuronal DNA damage and mitochondrial function (Onyango et al ., 2002; Shi et al ., 2005). As expected, ectopic expression of mito‐p53 induced significant (around 80%) neuronal DNA damage (indicating DNA fragmentation by DAPI staining) compared to control vector (DsRed)‐transfected neurons (around 20%) (Fig.…”

“…SIRTs (mammalian homolog of silent mating type information regulation 2 homolog in yeast) are a family of epigenetic mediators that play various functions in aging, chromatin integrity, metabolic regulation, and longevity (Kim et al ., 2007; Hirschey et al ., 2010). Among sirtuins, SIRT1 has been mostly widely studied and its level is changed in AD brains (Shi et al ., 2005; Someya et al ., 2010; Kim et al ., 2011). …”

“…It regulates mitochondrial activity by ROS in many cell types and modulates CREB phosphorylation and fat metabolism (Shi et al ., 2005; Hirschey et al ., 2010; Kim et al ., 2010). Importantly, SIRT3 has an essential role in enhancing the mitochondrial antioxidant glutathione, which could contribute to reduce aging in mammals (Someya et al ., 2010).…”

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

“…Mitochondria are essential for cell survival and their dysfunction has been involved in metabolic diseases such as age-associated disease, neurodegenerative diseases and cancer. Functional studies showed that SIRT3 regulates mitochondrial biogenesis, and it is correlated with the expression of genes related to mitochondrial function, including PGC1α and UCP1 (Kong et al, 2010;Shi et al, 2005). Moreover, SIRT3 deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status (Yu et al, 2012).…”

Sirtuins, nuclear hormone receptor acetylation and transcriptional regulation

“…Both SIRT3 and SIRT4 are imported into the mitochondrial matrix [44,45]. SIRT3 is required for expression of the uncoupling protein 1 (UCP-1) [46]. SIRT3 deacetylates and activates acetyl-coenzyme-A synthetase (AceSC2) [44,47], thereby facilitating the entry of acetate into the tricarboxylic acid (TCA) cycle.…”