DOCSLIB.ORG

PGC-1Α, Sirtuins and Parps in Huntington's Disease and Other

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PGC-1Α, Sirtuins and Parps in Huntington's Disease and Other Neurochemical Research (2019) 44:2423–2434 https://doi.org/10.1007/s11064-019-02809-1 ORIGINAL PAPER PGC‑1α, Sirtuins and PARPs in Huntington’s Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All Alejandro Lloret1,2 · M. Flint Beal1 Received: 28 January 2019 / Revised: 2 May 2019 / Accepted: 2 May 2019 / Published online: 7 May 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract In this review, we summarize the available published information on the neuroprotective efects of increasing nicotinamide adenine dinucleotide (NAD+) levels in Huntington’s disease models. We discuss the rationale of potential therapeutic beneft of administering nicotinamide riboside (NR), a safe and efective NAD+ precursor. We discuss the agonistic efect on the Sirtuin1-PGC-1α-PPAR pathway as well as Sirtuin 3, which converge in improving mitochondrial function, decreasing ROS production and ameliorating bioenergetics defcits. Also, we discuss the potential synergistic efect of increasing NAD+ combined with PARPs inhibitors, as a clinical therapeutic option not only in HD, but other neurodegenerative conditions. Keywords Huntington’s disease · NAD+ · Nicotinamide Riboside · Sirtruins · PGC-1 alpha · PARPs Introduction [1]. HD is characterized by striatal degeneration, behavio- ral and cognitive impairments, and involuntary choreiform Mitochondrial dysfunction and ROS production are a com- movements. The toxic efects of mHtt include transcriptional mon pathogenic features present among many neurodegen- dysregulation, oxidative damage, excitotoxicity and bioener- erative conditions, such as Alzheimer’s, Parkinson’s and getic defects [2–4]. One element in which all these pathways Huntington’s disease (HD). HD is an autosomal-dominant seem to converge is PGC-1α, whose activation is modulated, neurodegenerative disorder that is considered as the fag- among others, by the NAD+ dependent deacetylase Sirtuin ship for studying the pathogenic pathways involved in neural 1 (SIRT1). NAD+ cellular levels also regulate two other death as well as for devising therapeutic intervention strate- targets of interest in neurodegeneration: Sirtuin 3 (SIRT3), gies. This is because its monogenetic cause, the relative pre- and Poly (ADP-ribose) polymerase 1 (PARP1). SIRT3 is a cision to predict the age of onset, its neural specifcity and mitochondrial deacetylase that regulates mitochondrial tran- availability of diferent pre-clinical models that re-capitulate scription in response to ROS stress. PARP1 is a member of a the human phenotypes. More importantly, the number of family of enzymes that polymerize ADP ribose units using patients sufering from this condition for which there is no NAD+ as a substrate and transfers them to acceptor proteins current efective treatment or cure. The mutation consists in response to DNA damage, and events such as chromatin of an expansion of an unstable CAG repeat located in exon remodeling, nuclear transcription, and cellular death [5]. 1 of the gene IT15. This results in a poly-glutamine expan- Based on the role that NAD+ plays in all these pathways that sion (> 36) in the protein product, mutant huntingtin (mHtt) are altered in HD, we discuss the rationale for its potential therapeutic value. Special issue: In honor of Prof. VeraAdam-Vizi. PGC‑1α and HD * Alejandro Lloret [email protected] PGC-1α is a transcriptional co-factor involved in energy 1 Feil Family Brain and Mind Research Institute, Weill production and mitochondrial biogenesis, cellular respi- Cornell Medical College, 1400 York Street, 5th Floor, Room ration and ROS detoxifcation. Its activity is regulated in A-501, New York, NY 10065, USA diferent tissues through many stimuli such as: exercise, 2 Present Address: NeuCyte Pharmaceuticals, 1561 Industrial in the muscle; cold, in brown fat [6]; and fasting, in the Road, San Carlos, CA 94070, USA Vol.:(0123456789)1 3 2424 Neurochemical Research (2019) 44:2423–2434 liver [7]. It induces glucose uptake and fatty acid oxidation and glutathione peroxidase (GPx1) [37]. CREB regulates (muscle), adaptive thermogenesis (brown fat) and gluco- PGC-1α activity in response to H 2O2, and stimuli such as neogenesis and beta-oxidation of fatty acids (liver) [8–10]. exercise [8, 37, 38]. At a cellular level, there are diferent signaling path- Overexpression of PGC-1α in the N171-82Q HD trans- ways that control PGC-1α expression and activity. PGC-1α genic mice ameliorated motor defcits and it attenuated neu- increases its own expression by an auto-regulatory loop rodegeneration, partly by alleviating oxidative stress [39]. It [11]. Post-translational modifcations such as phosphoryla- also virtually eliminated huntingtin aggregates by activat- tion by AMPK and p38 MAPK; methylation by PRMT1 ing the transcription factor TFEB, a master regulator of the and de-acetylation by SIRT1 promote its activity [12]. autophagy-lysosome pathway. PGC-1α and PGC-1β overex- Phosphorylation by AKT and CLK2; SUMOylation by pression in rat cortical neurons co-transfected with a human SUMO1 and acetylation by GCN5 represses it [13–16]. huntingtin exon containing a 120 CAG expansion restores It is also modulated by cAMP, Ca2+ and CREB [17–20]. cell survival and increases mitochondrial density [40]. Indi- Key fndings reported in the literature point towards rect activation of PGC-1α by means of mitogen- and stress- PGC-1α as a key player in the pathogenesis of HD. activated kinase (MSK-1) [36], and by adipose-derived stem Sequence variation in the PGC-1α gene modifes age of cells (ASCs) exosomes [41] restores mitochondrial func- onset of HD [21–24]. Reported phenotype of PGC-1α tion. Next, we present the neuroprotective efect observed knockout mice show a spongiform pattern of neurode- by increasing active PGC-1α in HD through its modulation generation in the striatum, as well as a marked behavio- by sirtuins 1 and 3. ral hyperactivity phenotype reminiscent of HD [25, 26]. Also, defects in myelination are present in PGC-1α KO mice as well as in R6/2 and BACHD HD transgenic mouse Sirtuin 1 and Sirtuin 3 in HD models [27]. Striata from HD patients, knock-in HD mice, and striatal STHdhQ111 cells (a homozygous cell-based Sirtuins are a family of class III histone deacetylases whose HD model, [28]), show marked reductions in PGC-1α activity depends on NAD +. In humans, there are 7 known mRNA levels, and huntingtin interferes with the CREB/ sirtuins (SIRT1-7) classifed mainly by their cellular locali- TAF4 complex [29]. Expression of PGC-1α is reduced zation (reviewed [42, 43]). SIRT1 and SIRT3 are of special in medium spiny neurons and its down-regulation wors- interest in HD. ens behavioral and neuropathological abnormalities in a SIRT1 mRNA and protein levels are decreased in brain PGC-1α knock-out-/HD knock-in mice (PGC-1α KO/KI) tissue from HD patients [44, 45]. An important role of SIRT1 [29]. Microarray expression data from human brains from in mediating neuroprotection was reported when SIRT1 HD patients showed signifcant reductions in 24 out of 26 overexpression showed a protective efect against motor PGC-1α target genes [30]. PGC-1α mRNA is reduced in dysfunction, and cortical and striatal atrophy, and loss of N171-82Q HD mice. Signifcant hypothermia was found striatal neurons in both N171-82Q and BACHD transgenic in both N171-82Q and R6/2 HD mice, due to impaired mouse models of HD [46, 47]. Brain-specifc knockdown of PGC-1α induction of uncoupling protein 1 (UCP-1) [30]. SIRT1 exacerbated brain pathology while overexpression Stimulation of extra-synaptic NMDA receptors impairs protected in the R6/2 transgenic mouse model of HD [46]. the PGC-1α cascade in HD mice [31]. There is impaired The protective efect required the presence of TORC1. The PGC-1α and PGC-1β function in HD transgenic mice, and expression of BDNF, which is lowered in HD [48], was iden- in HD human muscle biopsies, and human myoblasts [32, tifed as a key target of SIRT1 and TORC1 transcriptional 33]. PGC-1β is a homologue of PGC-1α, which is abun- activity. Mutant Htt interfered with TORC1/CREB to repress dantly expressed in heart, skeletal muscle, brown adipose BDNF transcription, and SIRT1 rescued the defect both tissue and brain and is involved in mitochondrial biogen- in vitro and in vivo. Interestingly, another report shows that esis [34]. BDNF stimulates PGC-1α dependent mitochondrial biogen- There is a markedly impaired ability to upregulate esis and dendritic spine formation and synapses in the hip- PGC-1α in response to an energetic stress in HD transgenic pocampus [49]. In cell culture studies beta-catenin enhanced mice [32, 33]. Reductions in numbers of mitochondria in mutant huntingtin toxicity, whereas SIRT1 overexpression striatal spiny neurons that are HD pathologic grade-depend- protects and reduces FOXO and beta-catenin signaling, and ent correlate with reductions in PGC-1α and TFAM [35]. increases mitochondrial uncoupling protein expression [50]. Mitogen- and stress-activated protein kinase 1 (MSK-1), Treatment of R6/2 HD mouse model with Beta-Lapachone which upregulates PGC-1α, is deficient in the striatum (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran- of HD patients and mice [36]. PGC-1α reduces oxidative 5,6-dione), a small molecule obtained from the bark of the stress, by increasing expression of copper/zinc superox- Lapacho tree, increases the levels of expression of SIRT1 ide dismutase (SOD1), manganese SOD (SOD2), catalase and PGC-1α and ameliorates motor and mitochondrial 1 3 Neurochemical Research (2019) 44:2423–2434 2425 dysfunction [51]. Resveratrol, a phenolic compound found in an 82Q N-terminal Htt fragment), and the R6/2 HD mouse red grapes and red wine, activates SIRT1 and has been tested model [63]. Clinical trials in healthy controls [64] and HD in HD models. Resveratrol treatment of a C. elegans model patients showed that Selisistat is relatively well tolerated. of HD was neuroprotective through activation of SIRT1 and However, there was no evidence of its efcacy since there PGC-1α [52, 53].
Load more

Recommended publications
  • The Role of PARP1 in Monocyte and Macrophage
    cells Review The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors Maciej Sobczak 1, Marharyta Zyma 2 and Agnieszka Robaszkiewicz 1,* 1 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] 2 Department of Immunopathology, Medical University of Lodz, 7/9 Zeligowskiego, Bldg 2, Rm177, 90-752 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-6354449; Fax: +48-42-6354449 or +48-42-635-4473 Received: 4 August 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing.
    [Show full text]
  • Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence
    International Journal of Molecular Sciences Article Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence Noemi Sola-Sevilla 1, Ana Ricobaraza 2, Ruben Hernandez-Alcoceba 2 , Maria S. Aymerich 3,4, Rosa M. Tordera 1 and Elena Puerta 1,* 1 Pharmacology and Toxicology Department, Faculty of Pharmacy, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain; [email protected] (N.S.-S.); [email protected] (R.M.T.) 2 Gene Therapy Program CIMA, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain; [email protected] (A.R.); [email protected] (R.H.-A.) 3 Departamento de Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, 31008 Pamplona, Spain; [email protected] 4 Neuroscience Program CIMA, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain * Correspondence: [email protected] Abstract: Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our Citation: Sola-Sevilla, N.; results show that the specific overexpression of this isoform does not induce significant behavioral or Ricobaraza, A.; Hernandez-Alcoceba, molecular effects at short or long term in the control strain. Only a tendency towards a worsening in R.; Aymerich, M.S.; Tordera, R.M.; the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together Puerta, E.
    [Show full text]
  • Poly(ADP-Ribose) Polymerase-1 (PARP1) and P53 Labelling Index Correlates with Tumour Grade in Meningiomas
    Original article Poly(ADP-ribose) polymerase-1 (PARP1) and p53 labelling index correlates with tumour grade in meningiomas Tamás Csonka1, Balázs Murnyák1, Rita Szepesi2, Andrea Kurucz1, Álmos Klekner3, Tibor Hortobágyi1 1Division of Neuropathology, Institute of Pathology, 2Department of Neurology, 3Department of Neurosurgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Folia Neuropathol 2014; 52 (2): 111-120 DOI: 10.5114/fn.2014.43782 Abstract Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades accord- ing to the 2007 WHO Classification of Tumours of the Central Nervous System. p53, as one of the most potent tumour suppressor proteins, plays a role in nearly 50% of human tumours. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme with high ATP demand. It plays a role in apoptosis by activating an apoptosis inducing factor, and in necrosis by consuming NAD+ and ATP. Only PARP1 has been investigated in detail in tumours out of the 17 members of the PARP superfamily; however, its role has not been studied in meningiomas yet. The aim of this study was to determine the role of p53 and PARP1 in meningiomas of different grade and to establish whether there is any correlation between the p53 and PARP1 expression. Both PARP1 and p53 have been expressed in all examined meningiomas. PARP1 labelled grade II tumours with a higher intensity as compared to grade I and III neoplasms, respectively. An increased p53 expression was noted in grade III meningiomas. There was no statistical correlation between p53 and PARP1 expression. Our data indicate that both PARP1 and p53 activation is a feature in menin- giomas of higher grade, PARP1 overexpression being an early, whereas p53 overexpression, a late event in tumour progression.
    [Show full text]
  • PARP Inhibitors in Prostate Cancer–The Preclinical Rationale and Current Clinical Development
    G C A T T A C G G C A T genes Review PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development Verneri Virtanen 1, Kreetta Paunu 1, Johanna K. Ahlskog 2, Reka Varnai 3,4 , Csilla Sipeky 5 and Maria Sundvall 1,6,* 1 Institute of Biomedicine, and Cancer Research Laboratories, Western Cancer Centre FICAN West, University of Turku, FI-20520 Turku, Finland 2 Faculty of Science and Engineering, Åbo Akademi University, and Turku Bioscience, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland 3 Department of Primary Health Care, University of Pécs, H-7623 Pécs, Hungary 4 Faculty of Health Sciences, Doctoral School of Health Sciences, University of Pécs, H-7621 Pécs, Hungary 5 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland 6 Department of Oncology and Radiotherapy, Turku University Hospital, FI-20521 Turku, Finland * Correspondence: maria.sundvall@utu.fi; Tel.: +358-2-313-0000 Received: 3 June 2019; Accepted: 22 July 2019; Published: 26 July 2019 Abstract: Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination.
    [Show full text]
  • A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets
    biomolecules Review A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets Rubayat Islam Khan †, Saif Shahriar Rahman Nirzhor † and Raushanara Akter * Department of Pharmacy, BRAC University, 1212 Dhaka, Bangladesh; [email protected] (R.I.K.); [email protected] (S.S.R.N.) * Correspondence: [email protected]; Tel.: +880-179-8321-273 † These authors contributed equally to this work. Received: 10 June 2018; Accepted: 26 June 2018; Published: 29 June 2018 Abstract: Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings
    [Show full text]
  • Pan-Histone Deacetylase Inhibitors Regulate Signaling Pathways
    Majumdar et al. BMC Genomics 2012, 13:709 http://www.biomedcentral.com/1471-2164/13/709 RESEARCH ARTICLE Open Access Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cells Gipsy Majumdar1, Piyatilake Adris1, Neha Bhargava1, Hao Chen2 and Rajendra Raghow1,2* Abstract Background: We have shown previously that pan-HDAC inhibitors (HDACIs) m-carboxycinnamic acid bis-hydroxamide (CBHA) and trichostatin A (TSA) attenuated cardiac hypertrophy in BALB/c mice by inducing hyper-acetylation of cardiac chromatin that was accompanied by suppression of pro-inflammatory gene networks. However, it was not feasible to determine the precise contribution of the myocytes- and non-myocytes to HDACI-induced gene expression in the intact heart. Therefore, the current study was undertaken with a primary goal of elucidating temporal changes in the transcriptomes of cardiac myocytes exposed to CBHA and TSA. Results: We incubated H9c2 cardiac myocytes in growth medium containing either of the two HDACIs for 6h and 24h and analyzed changes in gene expression using Illumina microarrays. H9c2 cells exposed to TSA for 6h and 24h led to differential expression of 468 and 231 genes, respectively. In contrast, cardiac myocytes incubated with CBHA for 6h and 24h elicited differential expression of 768 and 999 genes, respectively. We analyzed CBHA- and TSA-induced differentially expressed genes by Ingenuity Pathway (IPA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Core_TF programs and discovered that CBHA and TSA impinged on several common gene networks. Thus, both HDACIs induced a repertoire of signaling kinases (PTEN-PI3K-AKT and MAPK) and transcription factors (Myc, p53, NFkB and HNF4A) representing canonical TGFβ, TNF-α, IFNγ and IL-6 specific networks.
    [Show full text]
  • Flawed Phospholipid Formation Or Faulty Fatty Acid Oxidation: Determining the Cause of Mitochondrial Dysfunction in Hearts Lacking Acsl1
    FLAWED PHOSPHOLIPID FORMATION OR FAULTY FATTY ACID OXIDATION: DETERMINING THE CAUSE OF MITOCHONDRIAL DYSFUNCTION IN HEARTS LACKING ACSL1 Trisha J. Grevengoed A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition (Biochemistry) in the School of Public Health. Chapel Hill 2015 Approved by: Rosalind A. Coleman Stephen D. Hursting Liza Makowski Leslie V. Parise Steven H. Zeisel © 2015 Trisha J. Grevengoed ALL RIGHTS RESERVED ii ABSTRACT Trisha J. Grevengoed: Fatty acid activation in cardiac mitochondria: The role of ACSL1 in phospholipid formation and remodeling, substrate switching, and autophagic flux (Under the direction of Rosalind A. Coleman) Cardiovascular disease is the number one cause of death worldwide. In the heart, mitochondria provide up to 95% of energy, with most of this energy coming from metabolism of fatty acids (FA). FA must be converted to acyl-CoAs by acyl-CoA synthetases (ACS) before entry into pathways of β- oxidation or glycerolipid synthesis. ACSL1 contributes more than 90% of total cardiac ACSL activity, and mice with an inducible knockout of ACSL1 (Acsl1T-/-) have impaired cardiac FA oxidation. The effects of loss of ACSL1 on mitochondrial respiratory function, phospholipid formation, or autophagic flux have not yet been studied. Acsl1T-/- hearts contained 3-fold more mitochondria with abnormal structure and displayed lower respiratory function. Because ACSL1 exhibited a strong substrate preference for linoleate (18:2), we investigated the composition of mitochondrial phospholipids. Acsl1T-/- hearts contained 83% less tetralinoleoyl-cardiolipin (CL), the major form present in control hearts.
    [Show full text]
  • Sirt3) Regulates Skeletal Muscle Metabolism and Insulin Signaling Via Altered Mitochondrial Oxidation and Reactive Oxygen Species Production
    Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production Enxuan Jinga, Brice Emanuellia, Matthew D. Hirscheyb,c, Jeremie Bouchera, Kevin Y. Leea, David Lombardd,1, Eric M. Verdinb,c, and C. Ronald Kahna,2 aJoslin Diabetes Center, Harvard Medical School, Boston, MA 02215; bGladstone Institute of Virology and Immunology, San Francisco, CA 94158; cUniversity of California, San Francisco, CA 94143; and dDepartment of Genetics, Harvard Medical School, Boston, MA Contributed by C. Ronald Kahn, July 20, 2011 (sent for review April 14, 2011) Sirt3 is a member of the sirtuin family of protein deacetylases that early, or even primary, contributor to development of skeletal is localized in mitochondria and regulates mitochondrial function. muscle insulin resistance and type 2 diabetes. Sirt3 expression in skeletal muscle is decreased in models of type 1 In recent years, the sirtuin family of NAD+-dependent and type 2 diabetes and regulated by feeding, fasting, and caloric deacetylases has emerged as important regulators of metabolism. restriction. Sirt3 knockout mice exhibit decreased oxygen con- Among seven members of the sirtuin family, Sirt3 is of particular sumption and develop oxidative stress in skeletal muscle, leading interest with regard to mitochondrial function because it is lo- to JNK activation and impaired insulin signaling. This effect is mim- calized primarily in mitochondria (16). Sirt3 has been shown to Sirt3 icked by knockdown of in cultured myoblasts, which exhibit deacetylate and thereby regulate several mitochondrial targets, reduced mitochondrial oxidation, increased reactive oxygen spe- including acetyl-CoA synthase 2 and glutamate dehydrogenase cies, activation of JNK, increased serine and decreased tyrosine (17, 18).
    [Show full text]
  • Assessment of Sirtuin 3 and Sirtuin 4 Level in Patients with Diabetes
    JCDP Sirtuins10.5005/jp-journals-10024-2405 in Diabetes and Periodontitis ORIGINAL RESEARCH Assessment of Sirtuin 3 and Sirtuin 4 Level in Patients with Diabetes Mellitus and Periodontitis: A Clinical Study 1Rashmi Laddha, 2Monica Mahajania, 3Amruta Khadse, 4Rajat Bajaj, 5Rashmi Jawade, 6Shashwati Choube ABSTRACT (6.37 ± 0.30). Mean fasting blood sugar (mg/dL) in group I was 80.40 ± 13.05, in group II, it was 160.40 ± 27.20, in group III, it Aim: Periodontitis is considered as infection in periodontal was 77.00 ± 12.78, and in group IV, it was 264.20 ± 53.17. The supporting structure leading to tooth mobility and ulcerated nonsignificant mean expression of SIRT 3 was seen in group I periodontal pockets. The present study was conducted to assess (29.20 ± 3.14), group II (29.19 ± 2.18), group III (28.89 ± 2.77), Sirtuin 3 (SIRT 3) and SIRT 4 level in patients with diabetes and group IV (29.59 ± 5.82). In group I, the mean level of SIRT mellitus (DM) and periodontitis. 4 was 28.93 ± 12.55, in group II, it was 28.82 ± 9.14, in group Materials and methods: The present study was conducted on III, it was 28.88 ± 6.03, and in group IV, it was 29.05 ± 10.68. 60 subjects. Subjects were divided into four groups, groups I to Conclusion: Association of DM and periodontitis is well known. IV. Each group comprised of 15 subjects. In all subjects, fasting The SIRT 3 and SIRT 4 are useful indicators of glycemic level blood glucose level was assessed.
    [Show full text]
  • P53-Dependent Cell Cycle Checkpoint After DNA Damage and Its
    Research and Review Insights Review Article ISSN: 2515-2637 p53-dependent cell cycle checkpoint after DNA damage and its relevance to PARP1 Tadashige Nozaki1* and Mitsuko Masutani2,3 1Department of Pharmacology, Faculty of Dentistry, Osaka Dental University, Japan 2Department of Frontier Life Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Japan 3Division of Cellular Signaling, Laboratory of Collaborative Research, National Cancer Center Research Institute, Japan Abstract The poly(ADP-ribose) polymerase (PARP) inhibitors, including 3-aminobenzamide (3-AB), suppress G1 arrest after DNA damage following gamma-irradiation, suggesting that PARP1, a major PARP family protein, is involved in the induction of G1 arrest. Furthermore, p53 stabilization following gamma-irradiation is not inhibited, but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM2 mRNA have been shown to be suppressed by 3-AB. Therefore, it is suggested that PARP1 participates as a downstream mediator of p53 dependent signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM2 mRNA expression. In this review, we discuss p53 cell cycle checkpoint after DNA damage, and its relevance to PARP1. Moreover, the role of PARP1 as a sensor of DNA damage will be proposed. Regulation of p53 and PARP1 activities is an attractive and promising target for the development of clinical treatments for particular diseases. Therefore, it is anticipated that the clinical application of drugs that specifically regulate PARP1 activity will develop in the near future. p53 and G1 checkpoint in cancer DNA damage owing to the abnormal transcriptional regulation by p53 [11,14]. Therefore, it is hypothesized that DNA damage accumulation During the development of cancer, multiple abnormalities occur causes mutated cells to progress into a cancer.
    [Show full text]
  • Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’S Ataxia Cardiomyopathy Model
    RESEARCH ARTICLE Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model Angelical S. Martin,1,2 Dennis M. Abraham,3 Kathleen A. Hershberger,1,2 Dhaval P. Bhatt,1 Lan Mao,3 Huaxia Cui,1 Juan Liu,2 Xiaojing Liu,2 Michael J. Muehlbauer,1 Paul A. Grimsrud,1 Jason W. Locasale,1,2 R. Mark Payne,4 and Matthew D. Hirschey1,2,5 1Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 2Department of Pharmacology and Cancer Biology, 3Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University Medical Center, Durham, North Carolina, USA. 4Department of Medicine, Division of Pediatrics, Indiana University, Indianapolis, Indiana, USA. 5Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Durham, North Carolina, USA. Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models.
    [Show full text]
  • Sirt3 Exerts Its Tumor-Suppressive Role by Increasing P53 and Attenuating Response to Estrogen in MCF-7 Cells
    antioxidants Article Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells 1, 1, 1 2 Marija Pinteri´c y, Iva I. Podgorski y , Marijana Popovi´cHadžija , Vedrana Fili´c , Mladen Paradžik 2,3 , Bastien Lucien Jean Proust 1, Ana Dekani´c 1 , Ivan Ciganek 1, Denis Pleše 1, Dora Marˇcinko 1, Tihomir Balog 1 and Sandra Soboˇcanec 1,* 1 Division of Molecular Medicine, Ruđer Boškovi´cInstitute, 10000 Zagreb, Croatia; [email protected] (M.P.); [email protected] (I.I.P.); [email protected] (M.P.H.); [email protected] (B.L.J.P.); [email protected] (A.D.); [email protected] (I.C.); [email protected] (D.P.); [email protected] (D.M.); [email protected] (T.B.) 2 Division of Molecular Biology, Ruđer Boškovi´cInstitute, 10000 Zagreb, Croatia; [email protected] (V.F.); [email protected] (M.P.) 3 Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre (MBC), University of Torino, 10124 Torino, Italy * Correspondence: [email protected]; Tel.: +385-1-4561-172 These authors contributed equally to this work. y Received: 25 February 2020; Accepted: 30 March 2020; Published: 1 April 2020 Abstract: Estrogen (E2) is a major risk factor for the initiation and progression of malignancy in estrogen receptor (ER) positive breast cancers, whereas sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, has the inhibitory effect on the tumorigenic properties of ER positive MCF-7 breast cancer cells. Since it is unclear if this effect is mediated through the estrogen receptor alpha (ERα) signaling pathway, in this study, we aimed to determine if the tumor-suppressive function of Sirt3 in MCF-7 cells interferes with their response to E2.
    [Show full text]