Sirt3 is a Sirtuin localized in the Mitochondria and acts as a Tumor Suppressor that regulates the global Acetylation landscape of mitochondrial proteins and reduces oxidative stress [23375372].

Sirt3 is highly enriched in Hematopoietic Stem Cells (HSCs) where it regulates a stress response. Sirt3 is dispensable for HSC maintenance and tissue homeostasis at a young age under homeostatic conditions but is essential under stress or at an old age. Sirt3 is suppressed with Aging. Upregulating of Sirt3 in aged HSCs improves their regenerative capacity [23375372].

Inactivating Sirt3 in mice makes no difference in young mice, but by the ripe old age of two, Sirt3-deficient mice have significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared to regular mice at the same age. It appears that in young cells, the blood stem cells are functioning well and have relatively low levels of oxidative stress, which is a burden of the body that results form the harmful byproducts of metabolism. At this youthful stage the body's normal antioxidant defenses can easily deal with the low stress levels. However at older age the system does not work as well and either more oxidative stress is generated or it can not remove it well, so levels build up. Under this condition, the normal antioxidative system cannot take care of it, that is probable when Srit3 is needed to boost the antioxidant system. Sirt3 levels drop with age [23375372].

Infusing blood stem cells of old mice with Sirt3 rejuvenates aged stem cells regenerative potential. Sirt3 is important in aged blood cells to cope with stress. Infusing blood stem cells of old mice with Sirt3 boosts the formation of new blood stem cells which indicates a reversal in the age-related decline in the old stem cells' function [23375372].

Sirt3 is a prominent regulator in Dietary Restriction adaptation by coordinately deacetylating proteins involved in diverse pathways of metabolism and mitochondrial maintenance [Hebert et al. 2012].

Sirt3 is essential for prevention of age-related hearing loss under DR [Someya et al 2010; Yu et al. 2012]. The expression of Sirt3 is in response to DR or prolonged fasting is considerably induced [Hirschey et al. 2010; Someya et al. 2010]. Sirt3 regulates the function of several mitochondrial proteins involved in oxidative phosphorylation, fatty acid oxidation, the urea cycle and the antioxidant response system [Hallows et al. 2006; Hallows et al. 2011; Hirschey et al. 2010; Lombard et al. 2008; Schwer et al. 2006; Shimazu et al. 2010; Yu et al. 2012]. Sirt3 is the main, if only, mitochondrial protein deacetylase. Sirt3 is stimulated under chronic DR [Hallows et al. 2011; Schwer et al 2009; Someya et al. 2010].

Acetylation reveals phosphorylation as a regulatory modification [Chen et al. 2012; Choudhary et al. 2009; Henriksen et al. 2012; Kim et al. 2006; Lundby et al 2012; Pagliarini et al. 2008; Zhao et al. 2010].

The mitochondrial proteome is extensively acetylated and pervasively altered by 25% DR and genetic loss of Sirt3. DR evokes changes in protein actylation predominately mitochondrial. While 33 proteins change their expression more than 1.5-fold, 108 acetylation sites change by 20% or greater. Changes in aceytlation, but not overall protein levels, drive metabolic reprogramming under DR [Hebert et al. 2012].

Majority of acetylation site with decreased acetylation in DR exhibit dramatically increased acetylation in Sirt3(-/-) [Hebert et al. 2012].

In wild-type mice DR considerably (5x) decreases acetyl-CoA in the liver. Sirt3(-/-) mice are unable to lower thier acetyl-CoA levels in response to DR. Ratios of acetyl-CoA/CoA display similar trends. Lower levels of acetyl-CoA during DR are consistent with increased acetyl-CoA utilization in energy requiring processes and indicates that Sirt3 reprograms the mitochondria toward efficient oxidative metabolism [Hebert et al. 2012].

Derive proteomic and post-translationl modifcation signatures from DR and Sirt3(-/-). Map those factors to the lifespan factors and indicate their expression/modification changes. Optionally derive a metabolic signature of Sirt3(-/-) and map those metabolites to the respective lifespan factors.


Someya, S., Yu, W., Hallows, W.C., Xu, J., Vann, J.M., Leeuwenburgh, C., Tanokura, M., Denu, J.M., and Prolla, T.A. (2010). Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812.

Yu, W., Dittenhafer-Reed, K.E., and Denu, J.M. (2012). SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J. Biol. Chem. 287, 14078–14086.

Hirschey, M.D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D.B., Grueter, C.A., Harris, C., Biddinger, S., Ilkayeva, O.R., et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125.

Hallows, W.C., Lee, S., and Denu, J.M. (2006). Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl. Acad. Sci. USA 103, 10230–10235.

Hallows, W.C., Yu, W., Smith, B.C., Devries, M.K., Ellinger, J.J., Someya, S., Shortreed, M.R., Prolla, T., Markley, J.L., Smith, L.M., et al. (2011). Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol. Cell 41, 139–149.

Lombard, D.B., Alt, F.W., Cheng, H.L., Bunkenborg, J., Streeper, R.S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., et al. (2007). Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807–8814.

Schwer, B., Bunkenborg, J., Verdin, R.O., Andersen, J.S., and Verdin, E. (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. USA 103, 10224–10229.

Shimazu, T., Hirschey, M.D., Hua, L., Dittenhafer-Reed, K.E., Schwer, B., Lombard, D.B., Li, Y., Bunkenborg, J., Alt, F.W., Denu, J.M., et al. (2010).

Chen, Y., Zhao, W., Yang, J.S., Cheng, Z., Luo, H., Lu, Z., Tan, M., Gu, W., and Zhao, Y. (2012). Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell. Proteomics 11, 1048–1062.

Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C., Olsen, J.V., and Mann, M. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840.

Henriksen, P., Wagner, S.A., Weinert, B.T., Sharma, S., Bacinskaja, G., Rehman, M., Juffer, A.H., Walther, T.C., Lisby, M., and Choudhary, C. (2012). Proteome-wide analysis of lysine acetylation suggests its broad regulatory scope in Saccharomyces cerevisiae. Mol. Cell. Proteomics, in press. Published online August 2, 2012. M112.017251.

Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., et al. (2006). Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618.

Lundby, A., Lage, K., Weinert, B.T., Bekker-Jensen, D.B., Secher, A., Skovgaard, T., Kelstrup, C.D., Dmytriyev, A., Choudhary, C., Lundby, C., et al. (2012). Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2, 419–431.

Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E., Walford, G.A., Sugiana, C., Boneh, A., Chen, W.K., et al. (2008). A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123.



Tags: mitochondria, dr, acetylation, proteomics, deacetylase, sirtuin, cr, diet
Update | Engage

Comment on This Data Unit