Nicotinamide adenine dinucleotide (NAD+) spans diverse roles in biology, serving as both an important redox cofactor in metabolism and a substrate for signaling enzymes that regulate protein post-translational modifications (PTMs).
Critical Issues:
Although the interactions between these different roles of NAD+ (and its reduced form NADH) have been considered, little attention has been paid to the role of compartmentation in these processes. Specifically, the role of NAD+ in metabolism is compartment specific (e.g., mitochondrial vs. cytosolic), affording a very different redox landscape for PTM-modulating enzymes such as sirtuins and poly(ADP-ribose) polymerases in different cell compartments. In addition, the orders of magnitude differences in expression levels between NAD+-dependent enzymes are often not considered when assuming the effects of bulk changes in NAD+ levels on their relative activities.
Recent Advances:
In this review, we discuss the metabolic, nonmetabolic, redox, and enzyme substrate roles of cellular NAD+, and the recent discoveries regarding the interplay between these roles in different cell compartments.
Future Directions:
Therapeutic implications for the compartmentation and manipulation of NAD+ biology are discussed. Antioxid. Redox Signal. 31, 623–642.
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References
1.
AbdelraheimSR, SpillerDG, and McLennanAG. Mammalian NADH diphosphatases of the Nudix family: cloning and characterization of the human peroxisomal NUDT12 protein. Biochem J, 374: 329–335, 2003.
2.
AbdelraheimSR, SpillerDG, and McLennanAG. Mouse Nudt13 is a mitochondrial Nudix hydrolase with NAD(P)H pyrophosphohydrolase activity. Protein J, 36: 425–432, 2017.
3.
AksoyP, WhiteTA, ThompsonM, and ChiniEN. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun, 345: 1386–1392, 2006.
4.
AliHR, AssiriMA, HarrisPS, MichelCR, YunY, MarentetteJO, HuynhFK, OrlickyDJ, ShearnCT, SabaLM, ReisdorphR, ReisdorphN, HirscheyMD, and FritzKS.Quantifying competition among mitochondrial protein acylation events induced by ethanol metabolism. J Proteome Res, 2019. [Epub ahead of print]; DOI: 10.1021/acs.jproteome.8b00800.
5.
BaiP.Biology of poly(ADP-Ribose) polymerases: the factotums of cell maintenance. Mol Cell, 58: 947–958, 2015.
6.
BaiP, CantoC, BrunyanszkiA, HuberA, SzantoM, CenY, YamamotoH, HoutenSM, KissB, OudartH, GergelyP, Menissier-de MurciaJ, SchreiberV, SauveAA, and AuwerxJ. PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab, 13: 450–460, 2011.
BarbosaMT, SoaresSM, NovakCM, SinclairD, LevineJA, AksoyP, and ChiniEN. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J, 21: 3629–3639, 2007.
9.
BelenkyP, BoganKL, and BrennerC. NAD+ metabolism in health and disease. Trends Biochem Sci, 32: 12–19, 2007.
10.
BelenkyP, ChristensenKC, GazzanigaF, PletnevAA, and BrennerC. Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. J Biol Chem, 284: 158–164, 2009.
11.
BenderDA.Biochemistry of tryptophan in health and disease. Mol Aspects Med, 6: 101–197, 1983.
12.
BergerF, LauC, DahlmannM, and ZieglerM. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem, 280: 36334–36341, 2005.
13.
BergerF, LauC, and ZieglerM. Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1. Proc Natl Acad Sci U S A, 104: 3765–3770, 2007.
14.
BessmanMJ, FrickDN, and O'HandleySF. The MutT proteins or “Nudix” hydrolases, a family of versatile, widely distributed, “housecleaning” enzymes. J Biol Chem, 271: 25059–25062, 1996.
15.
BiJ, WangH, and XieJ. Comparative genomics of NAD(P) biosynthesis and novel antibiotic drug targets. J Cell Physiol, 226: 331–340, 2011.
16.
BieganowskiP and BrennerC. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell, 117: 495–502, 2004.
17.
BillingtonRA, TravelliC, ErcolanoE, GalliU, RomanCB, GrollaAA, CanonicoPL, CondorelliF, and GenazzaniAA. Characterization of NAD uptake in mammalian cells. J Biol Chem, 283: 6367–6374, 2008.
18.
BlackerTS and DuchenMR. Investigating mitochondrial redox state using NADH and NADPH autofluorescence. Free Radic Biol Med, 100: 53–65, 2016.
19.
BlackerTS, MannZF, GaleJE, ZieglerM, BainAJ, SzabadkaiG, and DuchenMR. Separating NADH and NADPH fluorescence in live cells and tissues using FLIM. Nat Commun, 5: 3936, 2014.
20.
BlinovaK, LevineRL, BojaES, GriffithsGL, ShiZD, RuddyB, and BalabanRS. Mitochondrial NADH fluorescence is enhanced by complex I binding. Biochemistry, 47: 9636–9645, 2008.
21.
BoslettJ, ReddyN, AlzarieYA, and ZweierJL.Inhibition of CD38 with the thiazoloquin(az)olin(on)e 78c protects the heart against post-ischemic injury. J Pharmacol Exp Ther, 369: 55–64, 2019. Epub ahead of publication. DOI: 10.1124/jpet.118.254557.
22.
BruzzoneS, GuidaL, ZocchiE, FrancoL, and De FloraA. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J, 15: 10–12, 2001.
23.
CambronneXA, StewartML, KimD, Jones-BrunetteAM, MorganRK, FarrensDL, CohenMS, and GoodmanRH. Biosensor reveals multiple sources for mitochondrial NAD+. Science, 352: 1474–1477, 2016.
24.
CantoC, MenziesKJ, and AuwerxJ. NAD+ Metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab, 22: 31–53, 2015.
25.
CantoC, SauveAA, and BaiP. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med, 34: 1168–1201, 2013.
26.
CappelliniMD and FiorelliG. Glucose-6-phosphate dehydrogenase deficiency. Lancet, 371: 64–74, 2008.
27.
ChiniEN, ChiniCCS, Espindola NettoJM, de OliveiraGC, and van SchootenW. The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends Pharmacol Sci, 39: 424–436, 2018.
CollinsPB and ChaykinS. The management of nicotinamide and nicotinic acid in the mouse. J Biol Chem, 247: 778–783, 1972.
30.
ConfortiL, GilleyJ, and ColemanMP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci, 15: 394–409, 2014.
31.
CouillaultC, PujolN, ReboulJ, SabatierL, GuichouJF, KoharaY, and EwbankJJ. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol, 5: 488–494, 2004.
DavilaA, LiuL, ChellappaK, RedpathP, Nakamaru-OgisoE, PaolellaLM, ZhangZ, MigaudME, RabinowitzJD, and BaurJA. Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. Elife, 7: e33246, 2018.
34.
Di Lisa F and ZieglerM.Pathophysiological relevance of mitochondria in NAD+ metabolism. FEBS Lett, 492: 4–8, 2001.
35.
DikalovaAE, ItaniHA, NazarewiczRR, McMasterWG, FlynnCR, UzhachenkoR, FesselJP, GamboaJL, HarrisonDG, and DikalovSI. Sirt3 impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension. Circ Res, 121: 564–574, 2017.
36.
DuJ, ZhouY, SuX, YuJJ, KhanS, JiangH, KimJ, WooJ, KimJH, ChoiBH, HeB, ChenW, ZhangS, CerioneRA, AuwerxJ, HaoQ, and LinH. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science, 334: 806–809, 2011.
37.
DuanY, GrossRA, and SheuSS. Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol, 585: 741–758, 2007.
38.
DurkaczBW, OmidijiO, GrayDA, and ShallS. (ADP-ribose)n participates in DNA excision repair. Nature, 283: 593–596, 1980.
39.
EngelPC.Glutamate dehydrogenases: the why and how of coenzyme specificity. Neurochem Res, 39: 426–432, 2014.
40.
EscandeC, NinV, PriceNL, CapelliniV, GomesAP, BarbosaMT, O'NeilL, WhiteTA, SinclairDA, and ChiniEN. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62: 1084–1093, 2013.
41.
EssumanK, SummersDW, SasakiY, MaoX, DiAntonioA, and MilbrandtJ. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron, 93: 1334–1343 e5, 2017.
42.
FeliciR, LapucciA, RamazzottiM, and ChiarugiA. Insight into molecular and functional properties of NMNAT3 reveals new hints of NAD homeostasis within human mitochondria. PLoS One, 8: e76938, 2013.
43.
FinkelT, DengCX, and MostoslavskyR. Recent progress in the biology and physiology of sirtuins. Nature, 460: 587–591, 2009.
44.
FiresteinR, BlanderG, MichanS, OberdoerfferP, OginoS, CampbellJ, BhimavarapuA, LuikenhuisS, de CaboR, FuchsC, HahnWC, GuarenteLP, and SinclairDA. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One, 3: e2020, 2008.
45.
Fisher-WellmanKH, LinCT, RyanTE, ReeseLR, GilliamLA, CatheyBL, LarkDS, SmithCD, MuoioDM, and NeuferPD. Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochem J, 467: 271–280, 2015.
46.
FletcherRS, RatajczakJ, DoigCL, OakeyLA, CallinghamR, Da Silva XavierG, GartenA, ElhassanYS, RedpathP, MigaudME, PhilpA, BrennerC, CantoC, and LaveryGG. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab, 6: 819–832, 2017.
47.
FormentiniL, MoroniF, and ChiarugiA. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo. Biochem Pharmacol, 77: 1612–1620, 2009.
48.
GaravagliaS, BruzzoneS, CassaniC, CanellaL, AllegroneG, SturlaL, ManninoE, MilloE, De FloraA, and RizziM. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem J, 441: 131–141, 2012.
49.
GerdtsJ, BraceEJ, SasakiY, DiAntonioA, and MilbrandtJ. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science, 348: 453–457, 2015.
50.
GerdtsJ, SummersDW, MilbrandtJ, and DiAntonioA. Axon Self-Destruction: new Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron, 89: 449–460, 2016.
51.
GomesAP, PriceNL, LingAJ, MoslehiJJ, MontgomeryMK, RajmanL, WhiteJP, TeodoroJS, WrannCD, HubbardBP, MerckenEM, PalmeiraCM, de CaboR, RoloAP, TurnerN, BellEL, and SinclairDA. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155: 1624–1638, 2013.
52.
GranchiC.ATP citrate lyase (ACLY) inhibitors: an anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur J Med Chem, 157: 1276–1291, 2018.
53.
GriffithsMH, ThomasDP, XipellJM, and HopeRN. Thorotrast-induced bilateral carcinoma of the kidney. Pathology, 9: 43–48, 1977.
54.
GrivennikovaVG, GladyshevGV, and VinogradovAD. Allosteric nucleotide-binding site in the mitochondrial NADH:ubiquinone oxidoreductase (respiratory complex I). FEBS Lett, 585: 2212–2216, 2011.
55.
GrossCJ and HendersonLM. Digestion and absorption of NAD by the small intestine of the rat. J Nutr, 113: 412–420, 1983.
56.
GrozioA, MillsKF, YoshinoJ, BruzzoneS, SocialiG, TokizaneK, LeiHC, CunninghamR, SasakiY, MigaudME, and ImaiS-i. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab, 1: 47–57, 2019.
57.
GrozioA, SocialiG, SturlaL, CaffaI, SonciniD, SalisA, RaffaelliN, De FloraA, NencioniA, and BruzzoneS. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J Biol Chem, 288: 25938–25949, 2013.
58.
GuseAH.Calcium mobilizing second messengers derived from NAD. Biochim Biophys Acta, 1854: 1132–1137, 2015.
59.
HaferkampI, Schmitz-EsserS, LinkaN, UrbanyC, CollingroA, WagnerM, HornM, and NeuhausHE. A candidate NAD+ transporter in an intracellular bacterial symbiont related to Chlamydiae. Nature, 432: 622–625, 2004.
60.
HaigisMC, MostoslavskyR, HaigisKM, FahieK, ChristodoulouDC, MurphyAJ, ValenzuelaDM, YancopoulosGD, KarowM, BlanderG, WolbergerC, ProllaTA, WeindruchR, AltFW, and GuarenteL. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 126: 941–954, 2006.
61.
HaigisMC and SinclairDA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol, 5: 253–295, 2010.
62.
HanschmannEM, GodoyJR, BerndtC, HudemannC, and LilligCH. Thioredoxins, glutaredoxins, and peroxiredoxins—molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid Redox Signal, 19: 1539–1605, 2013.
63.
HaraN, YamadaK, ShibataT, OsagoH, and TsuchiyaM. Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS One, 6: e22781, 2011.
HornyakL, DobosN, KonczG, KaranyiZ, PallD, SzaboZ, HalmosG, and SzekvolgyiL. The role of indoleamine-2,3-dioxygenase in cancer development, diagnostics, and therapy. Front Immunol, 9: 151, 2018.
69.
HottigerMO, HassaPO, LuscherB, SchulerH, and Koch-NolteF. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci, 35: 208–219, 2010.
70.
HouJ, ChongZZ, ShangYC, and MaieseK. Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. Curr Neurovasc Res, 7: 95–112, 2010.
71.
HoutkooperRH, CantoC, WandersRJ, and AuwerxJ. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev, 31: 194–223, 2010.
72.
IntlekoferAM, DematteoRG, VennetiS, FinleyLW, LuC, JudkinsAR, RustenburgAS, GrinawayPB, ChoderaJD, CrossJR, and ThompsonCB. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab, 22: 304–311, 2015.
73.
IwaharaT, BonasioR, NarendraV, and ReinbergD. SIRT3 functions in the nucleus in the control of stress-related gene expression. Mol Cell Biol, 32: 5022–5034, 2012.
74.
JiangH, KhanS, WangY, CharronG, HeB, SebastianC, DuJ, KimR, GeE, MostoslavskyR, HangHC, HaoQ, and LinH. SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature, 496: 110–113, 2013.
75.
KaramanlidisG, LeeCF, Garcia-MenendezL, KolwiczSCJr., SuthammarakW, GongG, SedenskyMM, MorganPG, WangW, and TianR.Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab, 18: 239–250, 2013.
76.
KimD, NguyenMD, DobbinMM, FischerA, SananbenesiF, RodgersJT, DelalleI, BaurJA, SuiG, ArmourSM, PuigserverP, SinclairDA, and TsaiLH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J, 26: 3169–3179, 2007.
77.
KimHS, PatelK, Muldoon-JacobsK, BishtKS, Aykin-BurnsN, PenningtonJD, van der MeerR, NguyenP, SavageJ, OwensKM, VassilopoulosA, OzdenO, ParkSH, SinghKK, AbdulkadirSA, SpitzDR, DengCX, and GiusD. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell, 17: 41–52, 2010.
78.
KimW, DeikA, GonzalezC, GonzalezME, FuF, FerrariM, ChurchhouseCL, FlorezJC, JacobsSBR, ClishCB, and RheeEP.Polyunsaturated fatty acid desaturation is a mechanism for glycolytic NAD+ recycling. Cell Metab, 2019. [Epub ahead of print]; DOI: 10.1016/j.cmet.2018.12.023.
79.
KornbergA and PricerWEJr. On the structure of triphosphopyridine nucleotide. J Biol Chem, 186: 557–567, 1950.
80.
KrishnakumarR and KrausWL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell, 39: 8–24, 2010.
81.
KulikovaV, ShabalinK, NerinovskiK, DolleC, NiereM, YakimovA, RedpathP, KhodorkovskiyM, MigaudME, ZieglerM, and NikiforovA. Generation, release, and uptake of the NAD precursor nicotinic acid riboside by human cells. J Biol Chem, 290: 27124–27137, 2015.
82.
KwonHS, LimHW, WuJ, SchnolzerM, VerdinE, and OttM. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J Immunol, 188: 2712–2721, 2012.
83.
LernerF, NiereM, LudwigA, and ZieglerM. Structural and functional characterization of human NAD kinase. Biochem Biophys Res Commun, 288: 69–74, 2001.
84.
LiHJ, CheXM, ZhaoW, HeSC, ZhangZL, ChenR, FanL, and JiaZL. Diet-induced obesity promotes murine gastric cancer growth through a nampt/sirt1/c-myc positive feedback loop. Oncol Rep, 30: 2153–2160, 2013.
85.
LiY, YokotaT, GamaV, YoshidaT, GomezJA, IshikawaK, SasaguriH, CohenHY, SinclairDA, MizusawaH, and MatsuyamaS. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. Cell Death Differ, 14: 2058–2067, 2007.
LinSJ, FordE, HaigisM, LisztG, and GuarenteL. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev, 18: 12–16, 2004.
88.
LisztG, FordE, KurtevM, and GuarenteL. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem, 280: 21313–21320, 2005.
89.
LiuC, VyasA, KassabMA, SinghAK, and YuX. The role of poly ADP-ribosylation in the first wave of DNA damage response. Nucleic Acids Res, 45: 8129–8141, 2017.
90.
LiuC and YuX. ADP-ribosyltransferases and poly ADP-ribosylation. Curr Protein Pept Sci, 16: 491–501, 2015.
91.
LiuY, DentinR, ChenD, HedrickS, RavnskjaerK, SchenkS, MilneJ, MeyersDJ, ColeP, YatesJ, 3rd, OlefskyJ, GuarenteL, and MontminyM. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature, 456: 269–273, 2008.
92.
LoscalzoJ.Adaptions to hypoxia and redox stress: essential concepts confounded by misleading terminology. Circ Res, 119: 511–513, 2016.
93.
LunaA, AladjemMI, and KohnKW. SIRT1/PARP1 crosstalk: connecting DNA damage and metabolism. Genome Integr, 4: 6, 2013.
94.
LuoX and KrausWL. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev, 26: 417–432, 2012.
95.
LuoX, RyuKW, KimDS, NanduT, MedinaCJ, GupteR, GibsonBA, SoccioRE, YuY, GuptaRK, and KrausWL. PARP-1 controls the adipogenic transcriptional program by PARylating C/EBPbeta and modulating its transcriptional activity. Mol Cell, 65: 260–271, 2017.
96.
MalavasiF, DeaglioS, FunaroA, FerreroE, HorensteinAL, OrtolanE, VaisittiT, and AydinS. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev, 88: 841–886, 2008.
97.
MalavasiF, DeaglioS, ZaccarelloG, HorensteinAL, ChillemiA, AudritoV, SerraS, GandioneM, ZitellaA, and TizzaniA. The hidden life of NAD+-consuming ectoenzymes in the endocrine system. J Mol Endocrinol, 45: 183–191, 2010.
98.
MansourTE.Phosphofructokinase. Curr Top Cell Regul, 5: 1–46, 1972.
MeyerJG, D'SouzaAK, SorensenDJ, RardinMJ, WolfeAJ, GibsonBW, and SchillingB. Quantification of lysine acetylation and succinylation stoichiometry in proteins using mass spectrometric data-independent acquisitions (SWATH). J Am Soc Mass Spectrom, 27: 1758–1771, 2016.
101.
MichishitaE, ParkJY, BurneskisJM, BarrettJC, and HorikawaI. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell, 16: 4623–4635, 2005.
102.
MillsKF, YoshidaS, SteinLR, GrozioA, KubotaS, SasakiY, RedpathP, MigaudME, ApteRS, UchidaK, YoshinoJ, and ImaiSI. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab, 24: 795–806, 2016.
103.
MinkM, FogelgrenB, OlszewskiK, MaroyP, and CsiszarK. A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans. Genomics, 74: 234–244, 2001.
104.
MoralesJ, LiL, FattahFJ, DongY, BeyEA, PatelM, GaoJ, and BoothmanDA. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr, 24: 15–28, 2014.
105.
MracekT, DrahotaZ, and HoustekJ. The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochim Biophys Acta, 1827: 401–410, 2013.
NabokinaSM, KashyapML, and SaidHM. Mechanism and regulation of human intestinal niacin uptake. Am J Physiol Cell Physiol, 289: C97–C103, 2005.
108.
NadtochiySM, SchaferX, FuD, NehrkeK, MungerJ, and BrookesPS. Acidic pH is a metabolic switch for 2-hydroxyglutarate generation and signaling. J Biol Chem, 291: 20188–20197, 2016.
109.
NadtochiySM, WangYT, NehrkeK, MungerJ, and BrookesPS. Cardioprotection by nicotinamide mononucleotide (NMN): involvement of glycolysis and acidic pH. J Mol Cell Cardiol, 121: 155–162, 2018.
110.
NiereM, KernstockS, Koch-NolteF, and ZieglerM. Functional localization of two poly(ADP-ribose)-degrading enzymes to the mitochondrial matrix. Mol Cell Biol, 28: 814–824, 2008.
111.
NikiforovA, DolleC, NiereM, and ZieglerM. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J Biol Chem, 286: 21767–21778, 2011.
112.
OhashiK, KawaiS, and MurataK. Identification and characterization of a human mitochondrial NAD kinase. Nat Commun, 3: 1248, 2012.
113.
OldhamWM, ClishCB, YangY, and LoscalzoJ. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab, 22: 291–303, 2015.
114.
OsterlohJM, YangJ, RooneyTM, FoxAN, AdalbertR, PowellEH, SheehanAE, AveryMA, HackettR, LoganMA, MacDonaldJM, ZiegenfussJS, MildeS, HouYJ, NathanC, DingA, BrownRHJr., ConfortiL, ColemanM, Tessier-LavigneM, ZuchnerS, and FreemanMR.dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science, 337: 481–484, 2012.
OuteiroTF, MarquesO, and KazantsevA. Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta, 1782: 363–369, 2008.
117.
PacherP and SzaboC. Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev, 25: 235–260, 2007.
118.
PalegoL, BettiL, RossiA, and GiannacciniG. Tryptophan biochemistry: structural, nutritional, metabolic, and medical aspects in humans. J Amino Acids, 2016: 8952520, 2016.
119.
PalmieriF, RiederB, VentrellaA, BlancoE, DoPT, Nunes-NesiA, TrauthAU, FiermonteG, TjadenJ, AgrimiG, KirchbergerS, ParadiesE, FernieAR, and NeuhausHE. Molecular identification and functional characterization of Arabidopsis thaliana mitochondrial and chloroplastic NAD+ carrier proteins. J Biol Chem, 284: 31249–31259, 2009.
120.
PaolettiJ, AssairiL, GelinM, HuteauV, NahoriMA, DussurgetO, LabesseG, and PochetS. 8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode. Eur J Med Chem, 124: 1041–1056, 2016.
121.
Partida-SanchezS, Rivero-NavaL, ShiG, and LundFE. CD38: an ecto-enzyme at the crossroads of innate and adaptive immune responses. Adv Exp Med Biol, 590: 171–183, 2007.
122.
PatraS, GhoshS, BeraS, RoyA, RayS, and RayM. Molecular characterization of tumor associated glyceraldehyde-3-phosphate dehydrogenase. Biochemistry (Mosc), 74: 717–727, 2009.
123.
PetrelliR, FelczakK, and CappellacciL. NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications. Curr Med Chem, 18: 1973–1992, 2011.
124.
PetrelliR, ShamYY, ChenL, FelczakK, BennettE, WilsonD, AldrichC, YuJS, CappellacciL, FranchettiP, GrifantiniM, MazzolaF, Di StefanoM, MagniG, and PankiewiczKW. Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues. Bioorg Med Chem, 17: 5656–5664, 2009.
125.
PiccirellaS, CzegleI, LizakB, MargittaiE, SenesiS, PappE, CsalaM, FulceriR, CsermelyP, MandlJ, BenedettiA, and BanhegyiG. Uncoupled redox systems in the lumen of the endoplasmic reticulum. Pyridine nucleotides stay reduced in an oxidative environment. J Biol Chem, 281: 4671–4677, 2006.
126.
PillaiVB, SundaresanNR, KimG, GuptaM, RajamohanSB, PillaiJB, SamantS, RavindraPV, IsbatanA, and GuptaMP. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem, 285: 3133–3144, 2010.
127.
PittelliM, FeliciR, PitozziV, GiovannelliL, BigagliE, CialdaiF, RomanoG, MoroniF, and ChiarugiA. Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol Pharmacol, 80: 1136–1146, 2011.
128.
PittelliM, FormentiniL, FaracoG, LapucciA, RapizziE, CialdaiF, RomanoG, MonetiG, MoroniF, and ChiarugiA. Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J Biol Chem, 285: 34106–34114, 2010.
129.
PlattenM, von Knebel DoeberitzN, OezenI, WickW, and OchsK. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol, 5: 673, 2014.
130.
PreissJ and HandlerP. Biosynthesis of diphosphopyridine nucleotide. I. Identification of intermediates. J Biol Chem, 233: 488–492, 1958.
131.
PreissJ and HandlerP. Biosynthesis of diphosphopyridine nucleotide. II. Enzymatic aspects. J Biol Chem, 233: 493–500, 1958.
132.
QuaronaV, ZaccarelloG, ChillemiA, BrunettiE, SinghVK, FerreroE, FunaroA, HorensteinAL, and MalavasiF. CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin Cytom, 84: 207–217, 2013.
133.
RajamohanSB, PillaiVB, GuptaM, SundaresanNR, BirukovKG, SamantS, HottigerMO, and GuptaMP. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol, 29: 4116–4129, 2009.
134.
RajmanL, ChwalekK, and SinclairDA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab, 27: 529–547, 2018.
RevolloJR, GrimmAA, and ImaiS. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem, 279: 50754–50763, 2004.
137.
RineJ and HerskowitzI. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics, 116: 9–22, 1987.
138.
RodgersJT, LerinC, HaasW, GygiSP, SpiegelmanBM, and PuigserverP. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 434: 113–118, 2005.
139.
RonchiJA, FigueiraTR, RavagnaniFG, OliveiraHC, VercesiAE, and CastilhoRF. A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities. Free Radic Biol Med, 63: 446–456, 2013.
140.
RouleauM, PatelA, HendzelMJ, KaufmannSH, and PoirierGG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer, 10: 293–301, 2010.
141.
RustinP, ChretienD, ParfaitB, RotigA, and MunnichA. Nicotinamide adenine dinucleotides permeate through mitochondrial membranes in human Epstein-Barr virus-transformed lymphocytes. Mol Cell Biochem, 174: 115–119, 1997.
142.
RyuKW, NanduT, KimJ, ChallaS, DeBerardinisRJ, and KrausWL. Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. Science, 360: eaan5780, 2018.
143.
RzemR, Veiga-da-CunhaM, NoelG, GoffetteS, NassogneMC, TabarkiB, SchollerC, MarquardtT, VikkulaM, and Van SchaftingenE. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A, 101: 16849–16854, 2004.
144.
SaidHM, NabokinaSM, BalamuruganK, MohammedZM, UrbinaC, and KashyapML. Mechanism of nicotinic acid transport in human liver cells: experiments with HepG2 cells and primary hepatocytes. Am J Physiol Cell Physiol, 293: C1773–C1778, 2007.
145.
SalwayJG.Metabolism at a Glance. Chichester, United Kingdom: Wiley, 2017.
146.
SasakiY, NakagawaT, MaoX, DiAntonioA, and MilbrandtJ. NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion. Elife, 5: e19749, 2016.
147.
ScholzTD, LaughlinMR, BalabanRS, KupriyanovVV, and HeinemanFW. Effect of substrate on mitochondrial NADH, cytosolic redox state, and phosphorylated compounds in isolated hearts. Am J Physiol, 268: H82–H91, 1995.
148.
ScottI, WebsterBR, LiJH, and SackMN. Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1. Biochem J, 443: 655–661, 2012.
149.
ShackelfordRE, MayhallK, MaxwellNM, KandilE, and CoppolaD. Nicotinamide phosphoribosyltransferase in malignancy: a review. Genes Cancer, 4: 447–456, 2013.
150.
ShiF, LiY, LiY, and WangX. Molecular properties, functions, and potential applications of NAD kinases. Acta Biochim Biophys Sin (Shanghai), 41: 352–361, 2009.
151.
SmithB, SchaferXL, AmbeskovicA, SpencerCM, LandH, and MungerJ. Addiction to coupling of the Warburg effect with glutamine catabolism in cancer cells. Cell Rep, 17: 821–836, 2016.
152.
SmithWC and HarlandRM. Injected Xwnt-8 RNA acts early in Xenopus embryos to promote formation of a vegetal dorsalizing center. Cell, 67: 753–765, 1991.
153.
SocialiG, RaffaghelloL, MagnoneM, ZamporliniF, EmioniteL, SturlaL, BianchiG, VigliaroloT, NahimanaA, NencioniA, RaffaelliN, and BruzzoneS. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model. Oncotarget, 7: 2968–2984, 2016.
154.
SteinLR and ImaiS. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab, 23: 420–428, 2012.
155.
SzantoM, BrunyanszkiA, KissB, NagyL, GergelyP, ViragL, and BaiP. Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein. Cell Mol Life Sci, 69: 4079–4092, 2012.
156.
TakanagaH, MaedaH, YabuuchiH, TamaiI, HigashidaH, and TsujiA. Nicotinic acid transport mediated by pH-dependent anion antiporter and proton cotransporter in rabbit intestinal brush-border membrane. J Pharm Pharmacol, 48: 1073–1077, 1996.
157.
TannoM, KunoA, YanoT, MiuraT, HisaharaS, IshikawaS, ShimamotoK, and HorioY. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem, 285: 8375–8382, 2010.
158.
TempelW, RabehWM, BoganKL, BelenkyP, WojcikM, SeidleHF, NedyalkovaL, YangT, SauveAA, ParkHW, and BrennerC. Nicotinamide riboside kinase structures reveal new pathways to NAD+. PLoS Biol, 5: e263, 2007.
159.
TodiscoS, AgrimiG, CastegnaA, and PalmieriF. Identification of the mitochondrial NAD+ transporter in Saccharomyces cerevisiae. J Biol Chem, 281: 1524–1531, 2006.
160.
UedaK, OkaJ, NaruniyaS, MiyakawaN, and HayaishiO. Poly ADP-ribose glycohydrolase from rat liver nuclei, a novel enzyme degrading the polymer. Biochem Biophys Res Commun, 46: 516–523, 1972.
161.
UhlenM, FagerbergL, HallstromBM, LindskogC, OksvoldP, MardinogluA, SivertssonA, KampfC, SjostedtE, AsplundA, OlssonI, EdlundK, LundbergE, NavaniS, SzigyartoCA, OdebergJ, DjureinovicD, TakanenJO, HoberS, AlmT, EdqvistPH, BerlingH, TegelH, MulderJ, RockbergJ, NilssonP, SchwenkJM, HamstenM, von FeilitzenK, ForsbergM, PerssonL, JohanssonF, ZwahlenM, von HeijneG, NielsenJ, and PontenF. Proteomics. Tissue-based map of the human proteome. Science, 347: 1260419, 2015.
162.
van LoosdregtJ, VercoulenY, GuichelaarT, GentYY, BeekmanJM, van BeekumO, BrenkmanAB, HijnenDJ, MutisT, KalkhovenE, PrakkenBJ, and CofferPJ. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood, 115: 965–974, 2010.
163.
VassilopoulosA, PenningtonJD, AndressonT, ReesDM, BosleyAD, FearnleyIM, HamA, FlynnCR, HillS, RoseKL, KimHS, DengCX, WalkerJE, and GiusD. SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress. Antioxid Redox Signal, 21: 551–564, 2014.
164.
VeechRL, EgglestonLV, and KrebsHA. The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver. Biochem J, 115: 609–619, 1969.
165.
WagnerGR and HirscheyMD. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol Cell, 54: 5–16, 2014.
166.
WandersRJ and WaterhamHR, FerdinandusseS. Metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum. Front Cell Dev Biol, 3: 83, 2015.
167.
WangS, XingZ, VoslerPS, YinH, LiW, ZhangF, SignoreAP, StetlerRA, GaoY, and ChenJ. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke, 39: 2587–2595, 2008.
168.
WestphalCH, DippMA, and GuarenteL. A therapeutic role for sirtuins in diseases of aging?. Trends Biochem Sci, 32: 555–560, 2007.
169.
WiseDR, WardPS, ShayJE, CrossJR, GruberJJ, SachdevaUM, PlattJM, DeMatteoRG, SimonMC, and ThompsonCB. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A, 108: 19611–19616, 2011.
170.
XuW, YangH, LiuY, YangY, WangP, KimSH, ItoS, YangC, WangP, XiaoMT, LiuLX, JiangWQ, LiuJ, ZhangJY, WangB, FryeS, ZhangY, XuYH, LeiQY, GuanKL, ZhaoSM, and XiongY. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell, 19: 17–30, 2011.
171.
YanagisawaS, BakerJR, VuppusettyC, KogaT, ColleyT, FenwickP, DonnellyLE, BarnesPJ, and ItoK. The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure. PLoS One, 13: e0193921, 2018.
YeD, GuanKL, and XiongY. Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer, 4: 151–165, 2018.
174.
YingW.NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal, 10: 179–206, 2008.
175.
YingW, WeiG, WangD, WangQ, TangX, ShiJ, ZhangP, and LuH. Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. Front Biosci, 12: 2728–2734, 2007.
176.
YoshinoJ, MillsKF, YoonMJ, and ImaiS. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab, 14: 528–536, 2011.
177.
YuCP, SongYL, ZhuZM, HuangB, XiaoYQ, and LuoDY. Targeting TDO in cancer immunotherapy. Med Oncol, 34: 73, 2017.
178.
ZhangK, KimH, FuZ, QiuY, YangZ, WangJ, ZhangD, TongX, YinL, LiJ, WuJ, QiNR, HoutenSM, and ZhangR. Deficiency of the mitochondrial NAD kinase causes stress-induced hepatic steatosis in mice. Gastroenterology, 154: 224–237, 2018.
179.
ZhangR.MNADK, a novel liver-enriched mitochondrion-localized NAD kinase. Biol Open, 2: 432–438, 2013.
180.
ZhangT, BerrocalJG, FrizzellKM, GambleMJ, DuMondME, KrishnakumarR, YangT, SauveAA, and KrausWL. Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters. J Biol Chem, 284: 20408–20417, 2009.
