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1.  Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress 
Environmental Health Perspectives  2014;122(12):1271-1278.
Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation.
Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function.
Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting.
Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways.
Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.
Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418
doi:10.1289/ehp.1408418
PMCID: PMC4256704  PMID: 25127496
2.  SIRT6 recruits SNF2H to sites of DNA breaks, preventing genomic instability through chromatin remodeling 
Molecular cell  2013;51(4):454-468.
Summary
DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration and senescence. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the histone deacetylase SIRT6 is one of the earliest factors recruited to sites of Double-Strand Breaks (DSBs). SIRT6 recruits the ISWI-chromatin remodeler SNF2H to DSBs, and deacetylates focally histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors, such as 53BP1, BRCA1 and RPA. Remarkably, SIRT6 deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by increased DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a novel crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.
doi:10.1016/j.molcel.2013.06.018
PMCID: PMC3761390  PMID: 23911928
3.  SIRT6 Is Required for Normal Retinal Function 
PLoS ONE  2014;9(6):e98831.
The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod and cone photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin.
doi:10.1371/journal.pone.0098831
PMCID: PMC4045872  PMID: 24896097
4.  SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease 
Cell reports  2013;5(3):654-665.
SUMMARY
Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevents the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7 deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.
doi:10.1016/j.celrep.2013.10.007
PMCID: PMC3888240  PMID: 24210820
5.  Metabolism, Longevity and Epigenetics 
Metabolic homeostasis, as well as interventions that influence nutrients’ uptake, are well-established means to influence lifespan even in higher eukaryotes. Until recently, molecular mechanisms to explain such an effect remained scantily understood. Sirtuins represent a group of protein deacetylases that depend on the metabolic intermediate NAD+ as a co-factor for their function. For this reason they sense metabolic stress and in turn function at multiple levels to exert proper metabolic adaptation. Among other things, sirtuins could perform as histone deacetylases inducing epigenetic changes to modulate transcription and DNA repair. Recent studies indicate that beyond sirtuins, the activity of other chromatin modifiers, such as histone acetyl transferases (HATs), might also be tightly linked to the availability of their intermediate metabolite Acetyl-CoA. In this study, we will summarize current knowledge depicting emerging concepts indicating a close crosstalk between the epigenetic machineries able to sense metabolic stress, their adaptive metabolic responses and their potential role in longevity.
doi:10.1007/s00018-013-1295-3
PMCID: PMC3625512  PMID: 23467663
6.  A tale of metabolites: the crosstalk between chromatin and energy metabolism 
Cancer discovery  2013;3(5):497-501.
Mitochondrial metabolism influences histone and DNA modifications by retrograde signaling and activation of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this Perspective that epigenetic modifications might impinge on cellular metabolism by affecting the pool of acetyl-CoA and SAM.
doi:10.1158/2159-8290.CD-13-0059
PMCID: PMC3652636  PMID: 23658298
7.  Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction 
Antioxidants & Redox Signaling  2013;18(6):630-641.
Abstract
Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. Results: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD+-dependent deacetylase in the production of this chemokine. Innovation: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. Conclusions: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice. Antioxid. Redox Signal. 18, 630–641.
doi:10.1089/ars.2011.4487
PMCID: PMC3549207  PMID: 22452634
8.  MicroRNAs in metabolism and metabolic diseases 
Cold Spring Harbor symposia on quantitative biology  2011;76:10.1101/sqb.2011.76.011049.
Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the Sterol Regulatory Element-Binding Protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Intriguingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid β-oxidation genes CROT, HADHB and CPT1A, as well as the energy sensor AMPK, the NAD+-dependent sirtuin SIRT6, and the insulin signaling intermediate IRS-2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.
doi:10.1101/sqb.2011.76.011049
PMCID: PMC3880782  PMID: 22156303
9.  The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis 
Molecular cell  2012;48(6):900-913.
Summary
Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α’s activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers—particularly other sirtuins—can modulate PGC-1α acetylation is currently unknown. Herein we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5’s activity. Leprdb/Leprdb mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.
doi:10.1016/j.molcel.2012.09.030
PMCID: PMC3534905  PMID: 23142079
10.  THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM 
Cell  2012;151(6):1185-1199.
Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a novel tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, while transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. Using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size and aggressiveness of tumors. SIRT6 also functions as a novel regulator of ribosome metabolism by co-repressing MYC transcriptional activity. Lastly, SIRT6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.
doi:10.1016/j.cell.2012.10.047
PMCID: PMC3526953  PMID: 23217706
11.  Sirt6 regulates TNFα secretion via hydrolysis of long chain fatty acyl lysine 
Nature  2013;496(7443):110-113.
The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases1 and have been implicated in the regulation of transcription, genome stability, metabolism, and lifespan2, 3. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human Sirt6 efficiently removes long chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of Sirt6 reveals a large hydrophobic pocket that can accommodate long chain fatty acyl groups. We demonstrate further that Sirt6 promotes the secretion of tumor necrosis factor α (TNFα) by removing the fatty acyl modification on K19 and K20 of TNFα. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data suggest that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of Sirt6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of the previously ignored protein posttranslational modification.
doi:10.1038/nature12038
PMCID: PMC3635073  PMID: 23552949
12.  Recent progress in the biology and physiology of sirtuins 
Nature  2009;460(7255):587-591.
The sirtuins are a highly conserved family of NAD+-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.
doi:10.1038/nature08197
PMCID: PMC3727385  PMID: 19641587
13.  SIRT1 Activators: The Evidence STACks up 
Aging (Albany NY)  2013;5(3):142-143.
PMCID: PMC3629285  PMID: 23474671
14.  A SIRT1-LSD1 Co-repressor Complex Regulates Notch Target Gene Expression and Development 
Molecular cell  2011;42(5):689-699.
Summary
Epigenetic regulation of gene expression by histone-modifying co-repressor complexes is central to normal animal development. The NAD+-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 co-repressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans.
doi:10.1016/j.molcel.2011.04.020
PMCID: PMC3119599  PMID: 21596603
SIRT1; LSD1; co-repressor; Notch; chromatin modification
15.  Fine Tuning our Cellular Factories: Sirtuins in Mitochondrial Biology 
Cell metabolism  2011;13(6):621-626.
Sirtuins have emerged in recent years as critical regulators of metabolism, influencing numerous facets of energy and nutrient homeostasis. Here, we review recent advances on the role of this fascinating family of mammalian proteins, and their well orchestrated function in modulating mitochondrial activity.
doi:10.1016/j.cmet.2011.05.004
PMCID: PMC3111451  PMID: 21641544
17.  Sirtuins, Metabolism, and Cancer 
More than a decade ago, sirtuins were discovered as a highly conserved family of NAD+-dependent enzymes that extend lifespan in lower organisms. In mammals, sirtuins are key regulators of stress responses and metabolism, influencing a range of diseases, including diabetes, neurodegeneration, and cancer. In recent years, new functions of sirtuins have been characterized, uncovering the underlying mechanisms of their multifaceted role in metabolism. Here, we specifically review recent progress on the role of sirtuins in DNA repair and energy metabolism, further discussing the implication of sirtuins in the biology of cancer.
doi:10.3389/fphar.2012.00022
PMCID: PMC3282920  PMID: 22363287
SIRT1; SIRT6; SIRT3; Warburg effect; cancer metabolism; DNA repair; genomic instability; sirtuin biology
18.  SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity 
Cell metabolism  2010;12(1):78-87.
Summary
Feeding on high-calorie (HC) diets induces serious metabolic imbalances, including obesity. Understanding the mechanisms against excessive body weight gain is critical for developing effective anti-obesity strategies. Here, we show that lack of nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase SIRT1 in pro-opiomelanocortin (POMC) neurons causes hypersensitivity to diet-induced obesity due to reduced energy expenditure. The ability of leptin to properly engage the phosphoinositide 3-kinase (PI3K) signaling in POMC neurons and elicit remodeling of perigonadal white adipose tissue (WAT) is severely compromised in mutant mice. Also, electrophysiological and histomorphomolecular analyses indicate a selective reduction in sympathetic nerve activity and brown-fat-like characteristics in perigonadal WAT of mutant mice; suggesting a physiologically important role for POMC neurons in controlling this visceral fat depot. In summary, our results provide direct genetic evidence that SIRT1 in POMC neurons is required for normal autonomic adaptations against diet-induced obesity.
doi:10.1016/j.cmet.2010.05.010
PMCID: PMC2904327  PMID: 20620997
19.  SIRT6 
Transcription  2010;1(1):17-21.
Sirtuins are the mammalian homologs of the yeast histone deacetylase Sir2. In recent years, an ever-expanding picture has emerged indicating that these proteins (SIRT1-7) play broad functions in cellular stress resistance, genomic stability, energy metabolism, aging and tumorigenesis.1 Among members of this family, SIRT6 appears to have particular significance in regulating metabolism, DNA repair and lifespan.2–4 In this context, new research from our lab has established SIRT6 as a key regulator of glucose homeostasis.5 In this Point of View article, we will first highlight our recent findings, and then provide an indepth discussion of their implications in cancer and aging.
doi:10.4161/trns.1.1.12143
PMCID: PMC3035182  PMID: 21327158
SIRT6; chromatin deacetylase; glucose metabolism; epigenetic; regulation metabolism
20.  The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α 
Cell  2010;140(2):280.
Summary
SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance and lifespan. SIRT6 deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a co-repressor of the transcription factor Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6 deficient cells exhibit increased Hif1α activity and show increased glucose uptake with up-regulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a novel role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis, and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.
doi:10.1016/j.cell.2009.12.041
PMCID: PMC2821045  PMID: 20141841
21.  DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression 
Cell  2008;135(5):907-918.
Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin modifying proteins may be a conserved mechanism of aging in eukaryotes.
doi:10.1016/j.cell.2008.10.025
PMCID: PMC2853975  PMID: 19041753
epigenetics; sirtuin; chromatin; histone; DNA repair
22.  INTRACELLULAR NAD LEVELS REGULATE TNF-α PROTEIN SYNTHESIS IN A SIRTUIN-DEPENDENT MANNER 
Nature medicine  2009;15(2):206-210.
Uncontrolled TNF-α synthesis is known to play an important role in numerous inflammatory disorders, and multiple transcriptional and post-transcriptional regulatory mechanisms have therefore evolved to dampen the production of this important pro-inflammatory cytokine. By examining the anti-inflammatory properties of the vitamin B3 constituent nicotinamide, we have uncovered a novel regulatory pathway controlling TNF-α production. Exogenous nicotinamide inhibits TNF-α secretion through modulation of mRNA translation efficiency. Moreover, the capacity to produce TNF-α appears to be directly correlated with intracellular NAD levels, suggesting that a NAD-dependent biological event that can be inhibited by nicotinamide controls TNF-α synthesis in cells of the immune system. Sirtuins represent NAD-dependent deacetylases involved in regulation of gene expression in both mammals and yeasts, and are known to be inhibited by nicotinamide. We demonstrate herein that similarly to nicotinamide, structurally unrelated sirtuin inhibitors downregulate TNF-α secretion with minimal effect on TNF-α gene transcription. By over-expressing individual sirtuin members in cell lines transiently expressing TNF-α, we have identified SIRT6 as a sirtuin member able to upregulate TNF-α synthesis in vitro. In agreement with this finding, bone-marrow derived dendritic cells from SIRT6 KO mice display reduced TNF-α synthesis in response to CpG. Collectively, these data delineate a novel relationship between metabolism and the inflammatory response, by uncovering the role of SIRT6 in the control of TNF-α secretion.
doi:10.1038/nm.1906
PMCID: PMC2845476  PMID: 19151729
23.  Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE 
PLoS ONE  2009;4(11):e7897.
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
doi:10.1371/journal.pone.0007897
PMCID: PMC2774509  PMID: 19936064
24.  SIRT6 IN DNA REPAIR, METABOLISM, AND AGEING 
Journal of internal medicine  2008;263(2):128-141.
Ageing, or increased mortality with time, coupled with physiologic decline, is a nearly universal yet poorly understood biological phenomenon. Studies in model organisms suggest that two conserved pathways modulate longevity: DNA damage repair and insulin/Igf1-like signaling. In addition, homologs of yeast Sir2 – the sirtuins – regulate lifespan in diverse organisms. Here, we focus on one particular sirtuin, SIRT6. Mice lacking SIRT6 develop a degenerative disorder that in some respects mimics models of accelerated ageing [1]. We discuss how sirtuins in general and SIRT6 specifically relate to other evolutionarily conserved pathways affecting ageing, and how SIRT6 might function to ensure organismal homeostasis and normal lifespan.
doi:10.1111/j.1365-2796.2007.01902.x
PMCID: PMC2486832  PMID: 18226091
Ageing; DNA Damage; Metabolism
25.  Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation▿ †  
Molecular and Cellular Biology  2007;27(24):8807-8814.
Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.
doi:10.1128/MCB.01636-07
PMCID: PMC2169418  PMID: 17923681

Results 1-25 (25)