created on Dec. 4, 2012, 1:53 a.m. by Hevok & updated on Dec. 4, 2012, 1:53 a.m. by Hevok
Sirt3 is a prominent regulator in DR 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.
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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.
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