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

By Tong Shi, Fei Wang, Emily S. Stieren, Q. Tong. Journal of Biological Chemistry, 2005

736 citations recorded by the source corpus.

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-1α, 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-1α, indicating a major role of PGC-1α in the SIRT3 action. In addition, SIRT3 stimulates CREB phosphorylation, which reportedly activates PGC-1α 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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/a31eb793b76e11cf34367a910ea7eff7d9ed49ec

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. M. Haigis
2. L. Guarente
3. E. Verdin
4. M. Circu
5. T. Aw
6. V. Longo
7. Brian K. Kennedy
8. R. Mostoslavsky

In Physiology

1. E. Verdin
2. M. Haigis
3. M. Circu
4. T. Aw
5. L. Guarente
6. Brian K. Kennedy
7. V. Longo
8. R. Mostoslavsky

Citations in the corpus

• Role of ROS and RNS Sources in Physiological and Pathological Conditions (2016, background): “In turn, SIRT3 binds to, deacetylates, and activates mitochondrial enzymes, including MnSOD, through a posttranslational mechanism [345].”
• The mitochondrial energy transduction system and the aging process. (2007, background): “In summary, it seems that SIRT3 activates mitochondrial functions and has a role in the adaptive thermogenesis of brown adipose tissue (144).”
• Sirtuins: critical regulators at the crossroads between cancer and aging (2007, background): “CR also induces SIRT3 expression, but appears to decrease SIRT4 (Shi et al., 2005; Haigis et al., 2006).”
• REACTIVE OXYGEN SPECIES, CELLULAR REDOX SYSTEMS AND APOPTOSIS (2010, positive): “Sustained expression of Sirt3 induced thermogenesis in brown adipocytes through a decrease in mitochondrial membrane potential and enhanced ROS production [91].”
• Sirtuins in aging and age-related disease. (2006, background): “Notably Sirt3, a mitochondrial Sirtuin, is expressed largely in brown fat, suggesting a role for this deacetylase in adaptive thermogenesis (Shi et al., 2005).”
• Caloric restriction. (2011, background): “SIRT-3 is a member of the sirtuin family that is expressed in mitochondria and located on the mitochondrial inner membrane and also appears responsive to CR (Shi et al., 2005).”
• A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis (2008, background): “This is consistent with other reports demonstrating a dominant-negative effect of such inactivating mutations (9, 17, 18).”
• Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis (2010, background): “Additionally, overexpression of SIRT3 leads to increased PGC1a gene expression in HIB1B brown adipocytes [35].”
• SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. (2006, background): “SIRT3 has been reported to be upregulated by CR and cold exposure in brown fat, where it may alter the metabolic activity of this tissue (Shi et al., 2005).”
• Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. (2009, background): “In agreement with our results, its levels have been shown to be increased during mild stress conditions, such as CR (9).”
• Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “SIRT3 is expressed in brown adipose tissue and induced by cold exposure (Shi et al. 2005).”
• SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction (2007, methodology): “The NIH3T3 stable cells expressing SIRT2 or SIRT2 mutant were established using the pBabe retroviral system (Pear et al., 1993) as previously described (Shi et al., 2005).”
• Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation (2007, background): “Our results are in agreement with previous studies of SIRT3 mRNA expression (33).”
• Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. (2010, background): “CR induces an increase in SIRT3 expression (Palacios et al., 2009; Shi et al., 2005).”