Abstract

Acetylation 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.

Highlights

  • The concentrations of glutamine and GABA were lower in sirtuin 3 (SIRT3) KO brain compared to wild type (WT) brain

  • It was reported that SIRT3 is processed in the nucleus prior to translocation to mitochondria only under stress conditions [39], whereas another group reported that the long inactive form is processed in the mitochondria to the active short form [40]

  • We and other laboratories showed that SIRT3 is present exclusively in mitochondria in the brain or liver of naïve wild type mice [19,40,41], suggesting that SIRT3 is localized to brain mitochondria under normal, physiologic conditions

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Summary

Introduction

Post-translational modification of protein affects activity and is one of the primary tools used by cells to adjust their response to changes in metabolic demands [1]. Regulation of protein function through acetylation is recognized as a major factor in cellular responses initiated by pathologic situations [2]. Bioenergetic metabolism is greatly dependent on well-regulated mitochondrial function. Changes in mitochondrial protein acetylation have a significant impact on brain cells’ ability to respond to stress or pathologic conditions [3,4,5,6,7,8,9,10]

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