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Li Wang, Jing-Jing Li, Li-Yu Guo, Peipei Li, Zhiqiang Zhao, Haisheng Zhou, Li-Jun Di
Glucose and Glutamine are two essential ingredients for cell growth. However, it remains open for investigation whether there is a general mechanism that coordinates the consumption of glucose and glutamine in cancer cells. Glutamine is mainly metabolized through the glutaminolysis pathway and our previous report indicated that CtBP increases GDH activity and promotes glutaminolysis through repressing the expression of SIRT4, a well-known mitochondrion-located factor that inhibits glutaminolysis pathway. CtBP is known to be a sensor of intracellular metabolic status; we thus hypothesized that a consensus CtBP-SIRT4-GDH axis may mediate the crosstalk between glycolysis and glutaminolysis...
March 13, 2018: Oncogenesis
Chris Carrico, Jesse G Meyer, Wenjuan He, Brad W Gibson, Eric Verdin
Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non-enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD+ -dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5...
March 6, 2018: Cell Metabolism
Shengchao Li, Weiping Zheng
Sirtuins are a family of intracellular enzymes whose enzymatic activities include catalyzing the β-nicotinamide adenine dinucleotide (β-NAD+)-dependent Nɛ-acyl-lysine deacylation and the β-NAD+-dependent mono-ADP-ribosylation. Among the seven sirtuin family members (i.e., SIRT1-7) thus far identified in mammals including humans, we know SIRT1/2/3/5/6 better than SIRT4/7 as for their enzymatic activities and the cellular roles of the reactions they catalyze. This chapter will provide an updated account on the enzymology and biology of SIRT4 and SIRT7, the two less well-understood mammalian sirtuins...
2018: Progress in Molecular Biology and Translational Science
Jason G Wood, Bjoern Schwer, Priyan C Wickremesinghe, Davis A Hartnett, Lucas Burhenn, Meyrolin Garcia, Michael Li, Eric Verdin, Stephen L Helfand
Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
You-Lin Tain, Wei-Chia Lee, Kay L H Wu, Steve Leu, Julie Y H Chan
Widespread consumption of high-fructose and high-fat diets relates to the global epidemic of hypertension. Hypertension may originate from early life by a combination of prenatal and postnatal nutritional insults. We examined whether maternal high-fructose diet increases vulnerability to post-weaning high-fructose or high-fat diets induced hypertension in adult offspring and determined the underlying mechanisms. Pregnant Sprague-Dawley rats received regular chow (ND) or chow supplemented with 60% fructose (HFR) during the entire pregnancy and lactation periods...
January 9, 2018: Nutrients
Claudia M Wever, Dominique Geoffrion, Bruno M Grande, Stephen Yu, Miguel Alcaide, Maryse Lemaire, Yasser Riazalhosseini, Josée Hébert, Christina Gavino, Donald C Vinh, Tina Petrogiannis-Haliotis, Svetlana Dmitrienko, Koren K Mann, Ryan D Morin, Nathalie A Johnson
Relapse occurs in 10-40% of Burkitt lymphoma (BL) patients that have completed intensive chemotherapy regimens and is typically fatal. While treatment-naive BL has been characterized, the genomic landscape of BL at the time of relapse (rBL) has never been reported. Here, we present a genomic characterization of two rBL patients. The diagnostic samples had mutations common in BL, including MYC and CCND3. Additional mutations were detected at relapse, affecting important pathways such as NFκB (IKBKB) and MEK/ERK (NRAS) signaling, glutamine metabolism (SIRT4), and RNA processing (ZFP36L2)...
January 3, 2018: Leukemia & Lymphoma
Piotr Celichowski, Karol Jopek, Marta Szyszka, Marianna Tyczewska, Ludwik K Malendowicz, Marcin Rucinski
INTRODUCTION: Sirtuins are NAD dependent class III histone deacetylases. In adrenal cortex mitochondria are able to transform - via nicotinamide nucleotide transhydrogenase (NNT) - NAD into NADPH, which is required for steroidogenesis. These findings suggest that sirtuins expressed in mitochondria, Sirt3, Sirt4 and Sirt5, may be associated with adrenal steroidogenesis. Therefore, the purpose of this study was to characterize the expression of mitochondrial sirtuins (Sirt3-5) in individual compartments of rat adrenal cortex, their developmental regulation and to demonstrate whether their expression is dependent on adrenocorticotrophic hormone (ACTH) and Nampt (nicotinamide phosphoribosyltransferase also known as visfatin/PBEF), the rate-limiting enzyme in the regulation of mammalian NAD synthesis...
December 20, 2017: Folia Histochemica et Cytobiologica
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
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
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
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
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
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
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-)
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
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
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
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
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
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
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