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https://www.readbyqxmd.com/read/29138502/crystal-structures-of-the-mitochondrial-deacylase-sirtuin-4-reveal-isoform-specific-acyl-recognition-and-regulation-features
#1
Martin Pannek, Zeljko Simic, Matthew Fuszard, Marat Meleshin, Dante Rotili, Antonello Mai, Mike Schutkowski, Clemens Steegborn
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29081403/sirt4-interacts-with-opa1-and-regulates-mitochondrial-quality-control-and-mitophagy
#2
Alexander Lang, Ruchika Anand, Simone Altinoluk-Hambüchen, Hakima Ezzahoini, Anja Stefanski, Afshin Iram, Laura Bergmann, Jennifer Urbach, Philip Böhler, Jan Hänsel, Manuel Franke, Kai Stühler, Jean Krutmann, Jürgen Scheller, Björn Stork, Andreas S Reichert, Roland P Piekorz
The stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD(+)-dependent manner and is implicated in cellular senescence and aging. Here we reveal a novel function of SIRT4 in mitochondrial morphology/quality control and regulation of mitophagy. We report that moderate overexpression of SIRT4, but not its enzymatically inactive mutant H161Y, sensitized cells to mitochondrial stress. CCCP-triggered dissipation of the mitochondrial membrane potential resulted in increased mitochondrial ROS levels and autophagic flux, but surprisingly led to increased mitochondrial mass and decreased Parkin-regulated mitophagy...
October 29, 2017: Aging
https://www.readbyqxmd.com/read/29059204/alterations-of-sirtuins-in-mitochondrial-cytochrome-c-oxidase-deficiency
#3
Arne Björn Potthast, Theresa Heuer, Simone Johanna Warneke, Anibh Martin Das
BACKGROUND: Sirtuins are NAD+ dependent deacetylases, which regulate mitochondrial energy metabolism as well as cellular response to stress. The NAD/NADH-system plays a crucial role in oxidative phosphorylation linking sirtuins and the mitochondrial respiratory chain. Furthermore, sirtuins are able to directly deacetylate and activate different complexes of the respiratory chain. This prompted us to analyse sirtuin levels in skin fibroblasts from patients with cytochrome c-oxidase (COX) deficiency and to test the impact of different pharmaceutical activators of sirtuins (SRT1720, paeonol) to modulate sirtuins and possibly respiratory chain enzymes in patient cells in vitro...
2017: PloS One
https://www.readbyqxmd.com/read/28891317/the-role-of-sirtuins-in-antioxidant-and-redox-signaling
#4
Chandra K Singh, Gagan Chhabra, Mary Ann Ndiaye, Liz Mariely Garcia-Peterson, Nicholas J Mack, Nihal Ahmad
SIGNIFICANCE: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets...
October 20, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28820880/knock-out-of-a-mitochondrial-sirtuin-protects-neurons-from-degeneration-in-caenorhabditis-elegans
#5
Rachele Sangaletti, Massimo D'Amico, Jeff Grant, David Della-Morte, Laura Bianchi
Sirtuins are NAD⁺-dependent deacetylases, lipoamidases, and ADP-ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28768896/the-effects-of-graded-levels-of-calorie-restriction-xi-evaluation-of-the-main-hypotheses-underpinning-the-life-extension-effects-of-cr-using-the-hepatic-transcriptome
#6
Davina Derous, Sharon E Mitchell, Lu Wang, Cara L Green, Yingchun Wang, Luonan Chen, Jing-Dong J Han, Daniel E L Promislow, David Lusseau, Alex Douglas, John R Speakman
Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging. Different hypotheses have been proposed for its main mode of action. We quantified hepatic transcripts of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated the responses relative to these various hypotheses. Of the four main signaling pathways implied to be linked to the impact of CR on lifespan (insulin/insulin like growth factor 1 (IGF-1), nuclear factor-kappa beta (NF-ĸB), mechanistic target of rapamycin (mTOR) and sirtuins (SIRTs)), all the pathways except SIRT were altered in a manner consistent with increased lifespan...
July 31, 2017: Aging
https://www.readbyqxmd.com/read/28739840/mitochondrial-sirtuins-in-cardiometabolic-diseases
#7
REVIEW
Xiaoqiang Tang, Xiao-Feng Chen, Hou-Zao Chen, De-Pei Liu
Mitochondria are heterogeneous and essentially contribute to cellular functions and tissue homeostasis. Mitochondrial dysfunction compromises overall cell functioning, tissue damage, and diseases. The advances in mitochondrion biology increase our understanding of mitochondrial dynamics, bioenergetics, and redox homeostasis, and subsequently, their functions in tissue homeostasis and diseases, including cardiometabolic diseases (CMDs). The functions of mitochondria mainly rely on the enzymes in their matrix...
August 15, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28726069/loss-of-sirtuin-4-leads-to-elevated-glucose-and-leucine-stimulated-insulin-levels-and-accelerated-age-induced-insulin-resistance-in-multiple-murine-genetic-backgrounds
#8
Frank K Huynh, Xiaoke Hu, Zhihong Lin, James D Johnson, Matthew D Hirschey
Several inherited metabolic disorders are associated with an accumulation of reactive acyl-CoA metabolites that can non-enzymatically react with lysine residues to modify proteins. While the role of acetylation is well-studied, the pathophysiological relevance of more recently discovered acyl modifications, including those found in inherited metabolic disorders, warrants further investigation. We recently showed that sirtuin 4 (SIRT4) removes glutaryl, 3-hydroxy-3-methylglutaryl, 3-methylglutaryl, and 3-methylglutaconyl modifications from lysine residues...
July 19, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28707980/extranuclear-sirtuins-and-metabolic-stress
#9
Mahmoud-Sobhy Elkhwanky, Jukka Hakkola
SIGNIFICANCE: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation...
August 11, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28706576/adherence-to-the-mediterranean-diet-and-circulating-levels-of-sirtuin-4-in-obese-patients-a-novel-association
#10
Luigi Barrea, Giovanni Tarantino, Carolina Di Somma, Giovanna Muscogiuri, Paolo Emidio Macchia, Andrea Falco, Annamaria Colao, Silvia Savastano
PURPOSE: This study was aimed at evaluating sirtuin 4 (Sirt4) levels in obese individuals, in relation to their adherence to the Mediterranean diet (MD), a healthy dietary pattern characterized by high antioxidant capacity, and markers of visceral fat storage. SUBJECTS/METHODS: Forty-three obese patients (44% males; BMI: 36.7-58.8 kg/m(2)) were consecutively included. PREvención con DIeta MEDiterránea (PREDIMED) and the 7-day food records were used to assess the adherence to MD and dietary pattern, respectively...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#11
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28644956/sirt4-is-a-regulator-of-insulin-secretion
#12
Elma Zaganjor, Sejal Vyas, Marcia C Haigis
In a recent issue of Cell Metabolism, Anderson et al. (2017) report that SIRT4 regulates insulin sensitivity in the pancreas via activation of methylcrotonyl-CoA carboxylase 1 (MCCC1) by removal of dicarboxyacyl-lysine modifications. Thus, SIRT4 activates leucine catabolism and causes decreased secretion of insulin from the pancreas.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28587732/for-certain-sirt4-activities
#13
Surinder Kumar, David B Lombard
Despite the fact that SIRT4 regulates important biological processes, its primary enzymatic activity has remained ambiguous. A recent study by Anderson, Huynh et al. has uncovered deacylase activities of SIRT4 towards newly described lysine modifications derived from reactive acyl-CoAs generated in leucine catabolism.
July 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28582846/decreased-sirt4-protein-levels-in-endometrioid-adenocarcinoma-tissues-are-associated-with-advanced-ajcc-stage
#14
Xiaoxi Chen, Xiangwen Lai, Caixia Wu, Qingxin Tian, Tingting Lei, Jingye Pan, Guoyu Huang
BACKGROUND: Members of the SIRT family are a highly conserved family of NAD+-dependent enzymes, many of which (SIRT1-7) play an important role in tumor formation. Recently, several studies have suggested that SIRT4 not only regulates glutamine metabolism, but also serves as a tumor suppressor. There are no studies have assessed its clinical significance in endometrioid adenocarcinoma. METHODS: We investigated SIRT4 protein levels in endometrioid adenocarcinoma and its possible association with selected clinico-pathological parameters by immunohistochemical staining of a tissue microarray that included 65 endometrioid adenocarcinoma patients...
July 4, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28559847/high-sensitivity-of-sirt3-deficient-hearts-to-ischemia-reperfusion-is-associated-with-mitochondrial-abnormalities
#15
Rebecca M Parodi-Rullán, Xavier Chapa-Dubocq, Pedro J Rullán, Sehwan Jang, Sabzali Javadov
Aim: Sirtuins are NAD(+)-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3(-/-)) mice. Materials and Methods: Isolated and Langendorff-mode perfused hearts of WT and SIRT3(-/-) mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28380376/sirt4-is-a-lysine-deacylase-that-controls-leucine-metabolism-and-insulin-secretion
#16
Kristin A Anderson, Frank K Huynh, Kelsey Fisher-Wellman, J Darren Stuart, Brett S Peterson, Jonathan D Douros, Gregory R Wagner, J Will Thompson, Andreas S Madsen, Michelle F Green, R Michael Sivley, Olga R Ilkayeva, Robert D Stevens, Donald S Backos, John A Capra, Christian A Olsen, Jonathan E Campbell, Deborah M Muoio, Paul A Grimsrud, Matthew D Hirschey
Sirtuins are NAD(+)-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine...
April 4, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28230862/inactivation-of-lsd1-triggers-senescence-in-trophoblast-stem-cells-by-induction-of-sirt4
#17
Josefina Castex, Dominica Willmann, Toufike Kanouni, Laura Arrigoni, Yan Li, Marcel Friedrich, Michael Schleicher, Simon Wöhrle, Mark Pearson, Norbert Kraut, Michaël Méret, Thomas Manke, Eric Metzger, Roland Schüle, Thomas Günther
Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28123512/sirt4-overexpression-protects-against-diabetic-nephropathy-by-inhibiting-podocyte-apoptosis
#18
Jian-Xia Shi, Qi-Jin Wang, Hui Li, Qin Huang
Diabetic nephropathy is a diabetic complication associated with capillary damage and increased mortality. Sirtuin 4 (SIRT4) plays an important role in mitochondrial function and the pathogenesis of metabolic diseases, including aging kidneys. The aim of the present study was to investigate the association between SIRT4 and diabetic nephropathy in a glucose-induced mouse podocyte model. A CCK-8 assay showed that glucose simulation significantly inhibited podocyte proliferation in a time- and concentration-dependent manner...
January 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27992564/microrna-497-inhibits-cardiac-hypertrophy-by-targeting-sirt4
#19
Yimin Xiao, Xiaofei Zhang, Shihao Fan, Guanghao Cui, Zhenya Shen
Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to overload pressure of heart. From abundant studies, a conclusion is drawn that many microRNAs (miRNAs) are associated with cardiac hypertrophy and heart failure. To investigate the role of microRNA-497 (miR-497) in myocardial hypertrophy, two models were established in this study from cell level to integral level. Cardiac hypertrophy was induced by using angiotensin Ⅱ (Ang Ⅱ) in vitro and was created by transverse abdominal aortic constriction (TAC) in vivo...
2016: PloS One
https://www.readbyqxmd.com/read/27941873/sirt4-inhibits-malignancy-progression-of-nsclcs-through-mitochondrial-dynamics-mediated-by-the-erk-drp1-pathway
#20
L Fu, Q Dong, J He, X Wang, J Xing, E Wang, X Qiu, Q Li
SIRT4 is well-known for its deacetylase activity in energy metabolism, but little is known about its roles in carcinogenesis. We demonstrated that SIRT4 was decreased in 70 out of 133 non-small cell lung cancer (NSCLC) cases by immunohistochemical staining and localized in the mitochondria using confocal microscopy. Low levels of SIRT4 expression was correlated with tumor node metastasis (TNM) stage, histological type of tumor (adenocarcinoma), lymph nodal status, Ki-67 (proliferation index) and poor overall survival...
May 11, 2017: Oncogene
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