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: 9.81). 10/2008; 105(38):14447-52. DOI: 10.1073/pnas.0803790105
Source: PubMed

ABSTRACT 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.

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    • "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]. "
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    ABSTRACT: ScopeWe 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 resultsEGCG 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.ConclusionSIRT3 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.
    Molecular Nutrition & Food Research 02/2015; 59(2). DOI:10.1002/mnfr.201400485 · 4.91 Impact Factor
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    • "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). "
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    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.
    • "Although the over-expression of Sirt3 was found to protect differentiated PC12 cells from GD and OGD insults, and hydrogen peroxide induced cell death (Supplemental Fig. 8), the mechanism through which this protection arose remains speculative at present, and is most likely multi-faceted. For example, Sirt3 deacetylates and activates succinate dehydrogenase (Cimen et al., 2010; Finley et al., 2011), NADH dehydrogenase 1 alpha subcomplex subunit 9 (Ahn et al., 2008), and isocitrate dehydrogenase 2 (Schlicker et al., 2008). The activities of each of these factors directly or indirectly elevate cellular NADH and FADH 2 . "
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    ABSTRACT: Sirt3 is a mitochondrial sirtuin whose deacetylase activity regulates facets of oxidative metabolic efficiency, anti-oxidative capacity, and intra-mitochondrial signaling. In this study, we tested whether the over-expression of a human Sirt3-myc transgene in differentiated PC12 cells, a model of sympathetic catecholaminergic neurons, would affect the sensitivity of these cells to oxidative stress or trophic withdrawal insults. Expression analysis revealed the Sirt3-myc product was expressed as a 45 kilodalton pro-form, which localized primarily within the cytosol, and a 30 kilodalton processed form that localized predominantly within mitochondria. When subjected to acute glucose deprivation or acute oxygen-glucose deprivation, differentiated PC12 cells over-expressing Sirt3-myc displayed significantly lower levels of cytotoxicity, both at the end of the insult, and at different times following media reperfusion, than cells transfected with a control plasmid. Further, Sirt3-myc over-expression also protected differentiated PC12 cells from apoptosis induced by trophic withdrawal. Collectively, these data indicate that an elevation of Sirt3 is sufficient to protect neuronal PC12 cells from cytotoxic insults, and add to the growing evidence that Sirt3 could be targeted for neuroprotective intervention.
    Brain Research 10/2014; 1587. DOI:10.1016/j.brainres.2014.08.066 · 2.83 Impact Factor
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