A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

Ahn, Bong-Hyun; Kim, Hyun‐Seok; Song, Shiwei; Lee, In Hye; Liu, Jie; Vassilopoulos, Athanassios; Deng, Chu‐Xia; Finkel, Toren

doi:10.1073/pnas.0803790105

Cited by 1,136 publications

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“…However, despite a likely role for increased ROS production, it is not possible from the present study to determine whether impaired insulin secretion following SIRT3 knockdown occurred as a result of a primary defect in insulin secretion or as a consequence of increased beta cell apoptosis. The precise mechanisms governing increased ROS production in INS1 cells are unclear; however, in different tissues, SIRT3 has been reported to alter the acetylation status of a number of proteins linked to ROS production [20,23,[40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

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Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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Aims/hypothesis Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. Methods We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. Results SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on proinflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. Conclusions/interpretation Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

“…In addition to amplifying IL1β and ROS signalling, SIRT3 may also influence beta cell function and mass by other mechanisms, including deacetylation of Ku70 [46] and glutamate dehydrogenase [20,47], and the regulation of ATP production [41].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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“…Hyperacetylation of mitochondrial proteins have been observed in SIRT3 knock-out mice (13,55). Several key enzymes involved in energy production in the mitochondria have been identified as SIRT3 substrates.…”

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confidence: 99%

“…Deacetylate isocitrate dehydrogenase 2 oxidatively decarboxylates isocitrate to ␣-ketoglutarate while converting NAD ϩ to NADH that promotes regeneration of antioxidants. Recently, Ahn et al (55) reported that SIRT3 Ϫ/Ϫ mouse embryonic fibroblasts have decreased ATP levels and abnormal activity of Complex 1 of the electron transport chain. Mice lacking SIRT3 showed reduced basal levels of ATP in the heart, kidney, and liver.…”

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confidence: 99%

Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

Jin

Wei

Jiang

et al. 2009

Journal of Biological Chemistry

183

234

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SIRT3 is a major mitochondrial NAD؉ -dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD ؉ . In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD ؉ . These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.Sirtuins are class III histone deacetylases that couple lysine deacetylation with NAD ϩ hydrolysis and are highly conserved in prokaryotes and eukaryotes (1). Mammals possess seven sirtuins, SIRT1-7, that occupy different subcellular compartments such as the nucleus (SIRT1, -6, -7), cytoplasm (SIRT2), and the mitochondria (SIRT3, -4, and -5) (2). They deacetylate lysines not only on histone substrates (3, 4) but also on nonhistone substrates such as p53 tumor suppressor protein (5), Foxo transcription factors (6, 7), PGC-1␣ (8), ␣-tubulin (9), acetyl-CoA synthetases (10 -12), and glutamate dehydrogenase (13). SIRT4 and SIRT6 have been shown to have ADP-ribosyltransferase activity (14 -16). Sirtuins have been reported to play important roles in gene silencing (17), cell cycle regulation (18,19), metabolism (8, 10 -12, 14, 20 -22), apoptosis (5, 23, 24), the lifespan-extension effects of calorie restriction (25,26), and circadian rhythms (27)(28)(29)(30) (50), and SIRT5 (51). Sirtuins contain a conserved enzymatic core with two domains; that is, a large Rossmann fold domain that binds NAD ϩ and a small domain formed by two insertions of the large domain that binds to a zinc atom. The acetylated peptide substrate binds to the cleft between the two domains. Some of the known structures are apo structures with sirtuin protein alone, whereas others are bound to acetylated peptide substrate and/or NAD ϩ and its analogs. These structures revealed the mechanism of action for the deacetylation activity and substrate specificity.SIRT3 localizes in mitochondria (13, 52-54) and is a major mitochondrial deacetylase. Hyperacetylation of mitochondrial proteins have been observed in SIRT3 knock-out mice (13, 55). Several key enzymes involved in energy production in the mitochondria have been identified as SIRT3 substrates. Acetyl-CoA synthetase 2 (AceCS2) 2 converts acetate into acetyl-CoA in the mitochondria. Deacetyla...

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“…SIRT3, 4 and 5 are mitochondrial proteins. SIRT3 positively regulates the activity of the acetyl-Coenzyme A synthetase 2, leading to the production of acetyl-coenzyme A (Hallows et al 2006;Schwer et al 2006), and deacetylates complex I of the respiratory chain involved in ATP production (Ahn et al 2008). Thus, SIRT3 regulates energetic cell homeostasis.…”

Section: Hdac Isoformsmentioning

confidence: 99%

Histone deacetylase modulators provided by Mother Nature

et al. 2012

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Protein acetylation status results from a balance between histone acetyltransferase and histone deacetylase (HDAC) activities. Alteration of this balance leads to a disruption of cellular integrity and participates in the development of numerous diseases, including cancer. Therefore, modulation of these activities appears to be a promising approach for anticancer therapy. Histone deacetylase inhibitors (HDACi) are epigenetically active drugs that induce the hyperacetylation of lysine residues within histone and non-histone proteins, thus affecting gene expression and cellular processes such as proteinprotein interactions, protein stability, DNA binding and protein sub-cellular localization. Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death. Over the last 30 years, numerous synthetic and natural products, including a broad range of dietary compounds, have been identified as HDACi. This review focuses on molecules from natural origins modulating HDAC activities and presenting promising anticancer activities.

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A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

Cited by 1,136 publications

References 26 publications

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

Histone deacetylase modulators provided by Mother Nature

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