The Regulation of Mitochondrial Function by SIRT3

Summary

Principal Investigator: Qiang Tong
Affiliation: Texas Medical Center
Country: USA
Abstract: Dietary caloric restriction is the most potent intervention prolonging life span, as well as reducing age-related diseases, such as obesity and diabetes. Although the mechanism of caloric restriction is not clear, it might be due to the reduction of reactive oxygen species (ROS) by caloric restriction. Sir2, which possesses the NAD- dependent deacetylase and ADP-ribosyltransferase activities, mediates the effect of caloric restriction in yeast, C.elegans and fruit flies. We have demonstrated that the expression of SIRT3, one of the seven mammalian Sir2 homologs, is increased by caloric restriction and cold exposure in brown adipose. We have also shown that murine SIRT3 is localized to the mitochondria inner membrane. Forced expression of SIRT3 elevates cytoplasmic calcium and CREB phosphorylation, leading to an up-regulation of the expressions of PPARgamma coactivator PGC-1 alpha and UCP-1 in brown adipocytes or UCP3 in myocytes. The expression of SIRT3 decreases cellular ROS levels by 40% while increasing oxygen consumption. Mutations of either SIRT3 deacetylase or ADP-ribosylase activities abolish these effects. Interestingly, SIRT3 is down regulated in the brown adipose tissue of several genetically obese mice. Our yeast two- hybrid screening of SIRT3 identified an interaction with a subunit of the complex I of the electron transport chain, which is one of the major sites for ROS production. We hypothesize that SIRT3 regulates mitochondrial function and superoxide production through two pathways: direct interaction with mitochondria! complex I and regulation of a calcium signaling pathway leading to the expression of PGC-1 alpha and uncoupling proteins. Thus, SIRT3 might offer protection against mitochondrial oxidative stress under obesity and diabetes. Our long-term goal is to elucidate the molecular mechanism of SIRT3 action and establish SIRT3 as a drug target for treatments that would mimic caloric restriction's beneficial effects on obesity and diabetes, even aging. The following specific aims will be pursued. 1) To confirm and characterize the interaction between SIRT3 and mitochondrial complex I. 2) To investigate how mitochondrial SIRT3 regulates intracellular calcium signaling. 3) To characterize the effect of SIRT3 on mitochondrial superoxide production and hyperglycemia-induced oxidative stress. 4) To investigate the effect of SIRT3 on adipose oxidative stress during obesity and diabetes in vivo.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3
    Ligen Lin
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS ONE 9:e85636. 2014
  2. pmc SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma
    Fei Wang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 20:801-8. 2009
  3. pmc Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria
    Huseyin Cimen
    Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Biochemistry 49:304-11. 2010
  4. pmc NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10
    Yongjie Yang
    Children s Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 285:7417-29. 2010
  5. pmc Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle
    Orsolya M Palacios
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
    Aging (Albany NY) 1:771-83. 2009
  6. pmc Characterization of murine SIRT3 transcript variants and corresponding protein products
    Yongjie Yang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
    J Cell Biochem 111:1051-8. 2010
  7. pmc Murine Sirt3 protein isoforms have variable half-lives
    Yongjie Yang
    Children s Nutrition Research Center, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA
    Gene 488:46-51. 2011
  8. doi Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation
    F Wang
    Children s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA
    Oncogene 31:1546-57. 2012
  9. pmc Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production
    Ligen Lin
    US Department of Agriculture Agricultural Research Service Children s Nutrition Research Center, Houston, Texas, USA
    Am J Physiol Endocrinol Metab 302:E1550-9. 2012

Scientific Experts

  • Qiang Tong
  • Yongjie Yang
  • Ligen Lin
  • Fei Wang
  • Huseyin Cimen
  • Orsolya M Palacios
  • Keyun Chen
  • F Wang
  • Jack Lee Ward
  • Emine C Koc
  • Ke Yun Chen
  • Min Joon Han
  • Hasan Koc
  • Waed Abdel Khalek
  • Chantal Wrutniak-Cabello
  • Henry Yang
  • Beatrice Chabi
  • X Guan
  • Weijun Pang
  • K Chen
  • H K Lin
  • Jon Gengler
  • Q Tong
  • Yuxiang Sun
  • C H Chan
  • Laura Montier
  • Jian Hong Deng
  • David A Sinclair
  • Basil P Hubbard
  • Yidong Bai
  • Tong Shi
  • Laurie J Goodyear
  • Juan J Carmona
  • Yasuko Manabe
  • Shaday Michan

Detail Information

Publications9

  1. pmc Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3
    Ligen Lin
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS ONE 9:e85636. 2014
    ..In summary, these results suggest that SIRT3 regulates the formation of oxidative muscle fiber, improves muscle metabolic function, and reduces muscle mass, changes that mimic the effects of caloric restriction. ..
  2. pmc SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma
    Fei Wang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 20:801-8. 2009
    ..Overall, our results indicate that SIRT2 responds to nutrient deprivation and energy expenditure to maintain energy homeostasis by promoting lipolysis and inhibiting adipocyte differentiation...
  3. pmc Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria
    Huseyin Cimen
    Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Biochemistry 49:304-11. 2010
    ..Our findings constitute the first evidence of the regulation of Complex II activity by the reversible acetylation of the SdhA subunit as a novel substrate of the NAD(+)-dependent deacetylase, SIRT3...
  4. pmc NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10
    Yongjie Yang
    Children s Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 285:7417-29. 2010
    ....
  5. pmc Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle
    Orsolya M Palacios
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
    Aging (Albany NY) 1:771-83. 2009
    ....
  6. pmc Characterization of murine SIRT3 transcript variants and corresponding protein products
    Yongjie Yang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
    J Cell Biochem 111:1051-8. 2010
    ....
  7. pmc Murine Sirt3 protein isoforms have variable half-lives
    Yongjie Yang
    Children s Nutrition Research Center, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA
    Gene 488:46-51. 2011
    ..This suggests that heat shock proteins might play a role in the maintenance of Sirt3 protein stability...
  8. doi Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation
    F Wang
    Children s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA
    Oncogene 31:1546-57. 2012
    ..Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation...
  9. pmc Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production
    Ligen Lin
    US Department of Agriculture Agricultural Research Service Children s Nutrition Research Center, Houston, Texas, USA
    Am J Physiol Endocrinol Metab 302:E1550-9. 2012
    ..Therefore, PU.1 might be a mediator for obesity-induced adipose inflammation and insulin resistance...