Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity
MetadataShow full item record
AbstractAcetylation is a post-translational modification that regulates the activity of enzymes fundamentally involved in cellular and mitochondrial bioenergetic metabolism. NAD+ dependent deacetylase sirtuin 3 (SIRT3) is localized to mitochondria where it plays a key role in regulating acetylation of TCA cycle enzymes and the mitochondrial respiratory complexes. Although the SIRT3 target proteins in mitochondria have been identified, the effect of SIRT3 activity on mitochondrial glucose metabolism in the brain remains elusive. The impact of abolished SIRT3 activity on glucose metabolism was determined in SIRT3 knockout (KO) and wild type (WT) mice injected with [1,6-13C]glucose using ex vivo 13C-NMR spectroscopy. The 1H-NMR spectra and amino acid analysis showed no differences in the concentration of lactate, glutamate, alanine, succinate, or aspartate between SIRT3 KO and WT mice. However, glutamine, total creatine (Cr), and GABA were lower in SIRT3 KO brain. Incorporation of label from [1,6-13C]glucose metabolism into lactate or alanine was not affected in SIRT3 KO brain. However, the incorporation of the label into all isotopomers of glutamate, glutamine, GABA and aspartate was lower in SIRT3 KO brain, reflecting decreased activity of mitochondrial and TCA cycle metabolism in both neurons and astrocytes. This is most likely due to hyperacetylation of mitochondrial enzymes due to suppressed SIRT3 activity in the brain of SIRT3 KO mice. Thus, the absence of Sirt3 results in impaired mitochondrial oxidative energy metabolism and neurotransmitter synthesis in the brain. Since the SIRT3 activity is NAD+ dependent, these results might parallel changes in glucose metabolism under pathologic reduction in mitochondrial NAD+ pools.
knock out mouse
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/16750
- MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation.
- Authors: Zhang X, Ji R, Liao X, Castillero E, Kennel PJ, Brunjes DL, Franz M, Möbius-Winkler S, Drosatos K, George I, Chen EI, Colombo PC, Schulze PC
- Issue date: 2018 May 8
- Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.
- Authors: Jing E, O'Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, Bain JR, Lee KY, Verdin EM, Newgard CB, Gibson BW, Kahn CR
- Issue date: 2013 Oct
- Exogenous H<sub>2</sub>S reduces the acetylation levels of mitochondrial respiratory enzymes via regulating the NAD<sup>+</sup>-SIRT3 pathway in cardiac tissues of <i>db/db</i> mice.
- Authors: Sun Y, Teng Z, Sun X, Zhang L, Chen J, Wang B, Lu F, Liu N, Yu M, Peng S, Wang Y, Zhao D, Zhao Y, Ren H, Cheng Z, Dong S, Lu F, Zhang W
- Issue date: 2019 Aug 1
- Exogenous H<sub>2</sub>S switches cardiac energy substrate metabolism by regulating SIRT3 expression in db/db mice.
- Authors: Sun Y, Tian Z, Liu N, Zhang L, Gao Z, Sun X, Yu M, Wu J, Yang F, Zhao Y, Ren H, Chen H, Zhao D, Wang Y, Dong S, Xu C, Lu F, Zhang W
- Issue date: 2018 Apr
- Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts.
- Authors: Liang Q, Benavides GA, Vassilopoulos A, Gius D, Darley-Usmar V, Zhang J
- Issue date: 2013 Sep 1