Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447-14452

Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2008; 105(38):14447-52. DOI: 10.1073/pnas.0803790105
Source: PubMed


Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3(-/-) mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced >50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3(-/-) tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex I, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3(-/-) animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels.

Full-text preview

Available from:
    • "SIRT3 is an intramitochondrial protein that influences mitochondrial function and biogenesis (Gurd et al. 2011), insulin sensitivity (Jing et al. 2011), thermogenesis and mitochondrial fatty acid oxidation by promoting expression of mitochondrial genes (Shi et al. 2005), and by regulating the acetylation levels of metabolic enzymes, including acetyl-coenzyme A synthetase 2 (AceCS2) (Schwer et al. 2006; Hallows et al. 2006), long-chain acyl-coenzyme A dehydrogenase (LCAD) (Hirschey et al. 2010) and 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (Hirschey et al. 2011). SIRT3 also regulates ATP synthesis by deacetylating several proteins of the mitochondrial electron transport Complex I and II and also interacts with several TCA (Krebs) cycle enzymes (Ahn et al. 2008; Cimen et al. 2010). In line with this, our results showed that SIRT3 expression was associated with CS activity (r = 0.5, P < 0.05). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine if the expression of the mitochondrial biogenesis-regulating proteins SIRT1, SIRT3 and PGC-1alpha in human skeletal muscle is influenced by adiposity. Twenty-nine male subjects were recruited into three groups: control (n = 10), obese (n = 10) and post-obese (n = 9). Intentionally, groups were matched by age, aerobic capacity and in addition the control and post-obese groups also by BMI. Muscle biopsies were obtained from the m. deltoid and vastus lateralis. PGC-1alpha, SIRT1 and SIRT3 protein expression was analyzed by Western blot. PGC-1alpha, SIRT1 and SIRT3 protein expression was similar regardless of the level of adiposity. Only a main effect of group on SIRT1 protein showed a trend toward higher expression in post-obese than control and obese (P = 0.09). Despite similar muscle fiber-type composition (previously reported), PGC-1alpha, SIRT1 and SIRT3 protein expression was higher in leg compared to arm muscle in all groups (P < 0.05). This study shows that PGC-1alpha, SIRT1 and SIRT3 protein expression in basal conditions was not altered in humans with different levels of adiposity but similar aerobic capacity. The expression of PGC-1alpha, SIRT1 and SIRT3 was higher in vastus lateralis than in deltoid muscle, indicating that local rather than systemic factors prevail in regulating the level of expression of these proteins.
    No preview · Article · Aug 2015 · Arbeitsphysiologie
  • Source
    • "Sirtuin3 (SIRT3) plays an important role in maintaining mitochondrial redox balance [15]. SIRT3 physically interacts with at least one of the known subunits of Complex I, enhances activity by deacetylation, and reduces the formation of excess ROS [16]. Cytochrome c (CYC) is another important component of the electron transport chain that helps control ROS leakage, and SIRT3 activity is required for CYC mRNA expression [17] [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Scope: We have previously reported that the green tea catechin, (-)-epigallocatechin-3-gallate (EGCG), can induce oxidative stress in oral cancer cells but exerts antioxidant effects in normal cells. Here, we report that these differential prooxidative effects are associated with sirtuin 3 (SIRT3), an important mitochondrial redox modulator. Methods and results: EGCG rapidly induced mitochondria-localized reactive oxygen species in human oral squamous carcinoma cells (SCC-25, SCC-9) and premalignant leukoplakia cells (MSK-Leuk1), but not in normal human gingival fibroblast cells (HGF-1). EGCG suppressed SIRT3 mRNA and protein expression, as well as, SIRT3 activity in SCC-25 cells, whereas it increased SIRT3 activity in HGF-1 cells. EGCG selectively decreased the nuclear localization of the estrogen-related receptor α (ERRα), the transcription factor regulating SIRT3 expression, in SCC-25 cells. This indicates that EGCG may regulate SIRT3 transcription in oral cancer cells via ERRα. EGCG also differentially modulated the mRNA expressions of SIRT3-associated downstream targets including glutathione peroxidase 1 and superoxide dismutase 2 in normal and oral cancer cells. Conclusion: SIRT3 represents a novel potential target through which EGCG exerts differential prooxidant effects in cancer and normal cells. Our results provide new biomarkers to be further explored in animal studies.
    Full-text · Article · Feb 2015 · Molecular Nutrition & Food Research
  • Source
    • "Generally the protein complexes I–V of ETC and oxidative phosphorylation are found acetylated at 511 lysine residues (Kim et al., 2006). Various studies show that the two subunits NDUFA9 subunit of complex I of ETC and oligomycin sensitivity conferring protein (OSCP) of complex V of oxidative phosphorylation, which is found to be acetylated at lysine amino acid residue K139 (Ahn et al., 2008) physically interact with Sirt3. A study shows that the ATP5A1 and ATP5F1 subunits of complex V also interact with Sirt3 (Vassilopoulos et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The energy production and metabolic homeostasis are well-orchestrated networks of carbohydrate, lipid and protein metabolism. These metabolic pathways are integrated by a key cytoplasmic organelle, the mitochondria, leading to production of many metabolic intermediates and harvest cellular energy in the form of ATP. Sirtuins are a highly conserved family of proteins that mediate cellular physiology and energy demands in response to metabolic inputs. Mitochondria inhabit three main types of sirtuins classified as Sirt3, Sirt4 and Sirt5. These sirtuins regulate mitochondrial metabolic functions mainly through controlling post-translational modifications of mitochondrial protein. However, the biological mechanism involved in controlling mitochondrial metabolic functions is not well understood at this stage. In this review the current knowledge on how mitochondrial sirtuins govern mitochondrial functions including energy production, metabolism, biogenesis and their involvement in different metabolic pathways are discussed. The identifications of potential pharmacological targets of sirtuins in the mitochondria and the bioactive compounds that target mitochondrial sirtuins will increase our understanding on regulation of mitochondrial metabolism in normal and disease state.
    Full-text · Dataset · Dec 2014
Show more