Skip to main content

Advertisement

SpringerLink
Log in

Multi-targeted Effect of Nicotinamide Mononucleotide on Brain Bioenergetic Metabolism

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Dysfunctions in NAD+ metabolism are associated with neurodegenerative diseases, acute brain injury, diabetes, and aging. Loss of NAD+ levels results in impairment of mitochondria function, which leads to failure of essential metabolic processes. Strategies to replenish depleted NAD+ pools can offer significant improvements of pathologic states. NAD+ levels are maintained by two opposing enzymatic reactions, one is the consumption of NAD+ while the other is the re-synthesis of NAD+. Inhibition of NAD+ degrading enzymes, poly-ADP-ribose polymerase 1 (PARP1) and ectoenzyme CD38, following brain ischemic insult can provide neuroprotection. Preservation of NAD+ pools by administration of NAD+ precursors, such as nicotinamide (Nam) or nicotinamide mononucleotide (NMN), also offers neuroprotection. However, NMN treatment demonstrates to be a promising candidate as a therapeutic approach due to its multi-targeted effect acting as PARP1 and CD38 inhibitor, sirtuins activator, mitochondrial fission inhibitor, and NAD+ supplement. Many neurodegenerative diseases or acute brain injury activate several cellular death pathways requiring a treatment strategy that will target these mechanisms. Since NMN demonstrated the ability to exert its effect on several cellular metabolic pathways involved in brain pathophysiology it seems to be one of the most promising candidates to be used for successful neuroprotection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Berger F, Ramirez-Hernandez MH, Ziegler M (2004) The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci 29:111–118

    Article  CAS  PubMed  Google Scholar 

  2. Belenky P, Bogan KL, Brenner C (2007) NAD + metabolism in health and disease. Trends Biochem Sci 32:12–19

    Article  CAS  PubMed  Google Scholar 

  3. Houtkooper RH, Canto C, Wanders RJ, Auwerx J (2010) The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev 31:194–223

    Article  CAS  PubMed  Google Scholar 

  4. Imai S, Guarente L (2014) NAD + and sirtuins in aging and disease. Trends Cell Biol 24:464–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Owens K, Park JH, Schuh R, Kristian T (2013) Mitochondrial dysfunction and NAD + metabolism alterations in the pathophysiology of acute brain injury. Transl Stroke Res 4:618–634

    Article  CAS  PubMed  Google Scholar 

  6. Klimova N, Long A, Kristian T (2018) Significance of mitochondrial protein post-translational modifications in pathophysiology of brain injury. Transl Stroke Res 9:223–237

    Article  PubMed  Google Scholar 

  7. Gholson RK (1966) The pyridine nucleotide cycle. Nature 212:933–935

    Article  CAS  PubMed  Google Scholar 

  8. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab 17:1143–1151

    Article  CAS  PubMed  Google Scholar 

  9. Szabo C, Dawson VL (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–298

    Article  CAS  PubMed  Google Scholar 

  10. Whalen MJ, Clark RS, Dixon CE, Robichaud P, Marion DW, Vagni V, Graham SH, Virag L, Hasko G, Stachlewitz R, Szabo C, Kochanek PM (1999) Reduction of cognitive and motor deficits after traumatic brain injury in mice deficient in poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 19:835–842

    Article  CAS  PubMed  Google Scholar 

  11. Chiarugi A, Moskowitz MA (2003) Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem 85:306–317

    Article  CAS  PubMed  Google Scholar 

  12. Yang J, Klaidman LK, Nalbandian A, Oliver J, Chang ML, Chan PH, Adams JD Jr (2002) The effects of nicotinamide on energy metabolism following transient focal cerebral ischemia in Wistar rats. Neurosci Lett 333:91–94

    Article  CAS  PubMed  Google Scholar 

  13. Ayoub IA, Lee EJ, Ogilvy CS, Beal MF, Maynard KI (1999) Nicotinamide reduces infarction up to two hours after the onset of permanent focal cerebral ischemia in Wistar rats. Neurosci Lett 259:21–24

    Article  CAS  PubMed  Google Scholar 

  14. Mokudai T, Ayoub IA, Sakakibara Y, Lee EJ, Ogilvy CS, Maynard KI (2000) Delayed treatment with nicotinamide (vitamin B(3)) improves neurological outcome and reduces infarct volume after transient focal cerebral ischemia in Wistar rats. Stroke 31:1679–1685

    Article  CAS  PubMed  Google Scholar 

  15. Park JH, Long A, Owens K, Kristian T (2016) Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol Dis 95:102–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA (2015) Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol 15:19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15:522–530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wei CC, Kong YY, Li GQ, Guan YF, Wang P, Miao CY (2017) Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway. Sci Rep 7:717

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Wei CC, Kong YY, Hua X, Li GQ, Zheng SL, Cheng MH, Wang P, Miao CY (2017) NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. Br J Pharmacol 174:3823–3836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J (2014) Nicotinamide mononucleotide, an intermediate of NAD + synthesis, protects the heart from ischemia and reperfusion. PLoS ONE 9:e98972

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Strosznajder RP, Czubowicz K, Jesko H, Strosznajder JB (2010) Poly(ADP-ribose) metabolism in brain and its role in ischemia pathology. Mol Neurobiol 41:187–196

    Article  CAS  PubMed  Google Scholar 

  22. Dawson VL (2005) Inhibition of poly(adenosine diphosphate-ribose) polymerase (PARP) in experimental models of neurologic diseases: cell death prevention. Retina 25:S31–S32

    Article  PubMed  Google Scholar 

  23. Althaus FR, Kleczkowska HE, Malanga M, Muntener CR, Pleschke JM, Ebner M, Auer B (1999) Poly ADP-ribosylation: a DNA break signal mechanism. Mol Cell Biochem 193:5–11

    Article  CAS  PubMed  Google Scholar 

  24. Kauppinen TM, Swanson RA (2007) The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145:1267–1272

    Article  CAS  PubMed  Google Scholar 

  25. Ha HC, Snyder SH (2000) Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 7:225–239

    Article  CAS  PubMed  Google Scholar 

  26. Dawson VL, Dawson TM (2004) Deadly conversations: nuclear-mitochondrial cross-talk. J Bioenerg Biomembr 36:287–294

    Article  CAS  PubMed  Google Scholar 

  27. Davidovic L, Vodenicharov M, Affar EB, Poirier GG (2001) Importance of poly(ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism. Exp Cell Res 268:7–13

    Article  CAS  PubMed  Google Scholar 

  28. Brochu G, Shah GM, Poirier GG (1994) Purification of poly(ADP-ribose) glycohydrolase and detection of its isoforms by a zymogram following one- or two-dimensional electrophoresis. Anal Biochem 218:265–272

    Article  CAS  PubMed  Google Scholar 

  29. Di Meglio S, Denegri M, Vallefuoco S, Tramontano F, Scovassi AI, Quesada P (2003) Poly(ADPR) polymerase-1 and poly(ADPR) glycohydrolase level and distribution in differentiating rat germinal cells. Mol Cell Biochem 248:85–91

    Article  PubMed  Google Scholar 

  30. Cozzi A, Cipriani G, Fossati S, Faraco G, Formentini L, Min W, Cortes U, Wang ZQ, Moroni F, Chiarugi A (2006) Poly(ADP-ribose) accumulation and enhancement of postischemic brain damage in 110-kDa poly(ADP-ribose) glycohydrolase null mice. J Cereb Blood Flow Metab 26:684–695

    Article  CAS  PubMed  Google Scholar 

  31. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103:18308–18313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Formentini L, Arapistas P, Pittelli M, Jacomelli M, Pitozzi V, Menichetti S, Romani A, Giovannelli L, Moroni F, Chiarugi A (2008) Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death. Br J Pharmacol 155:1235–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Blenn C, Althaus FR, Malanga M (2006) Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death. Biochem J 396:419–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lu XC, Massuda E, Lin Q, Li W, Li JH, Zhang J (2003) Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. Brain Res 978:99–103

    Article  CAS  PubMed  Google Scholar 

  35. Burns DM, Ying W, Kauppinen TM, Zhu K, Swanson RA (2009) Selective down-regulation of nuclear poly(ADP-ribose) glycohydrolase. PLoS ONE 4:e4896

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Schuber F, Lund FE (2004) Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Curr Mol Med 4:249–261

    Article  CAS  PubMed  Google Scholar 

  37. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88:841–886

    Article  CAS  PubMed  Google Scholar 

  38. Aksoy P, White TA, Thompson M, Chini EN (2006) Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun 345:1386–1392

    Article  CAS  PubMed  Google Scholar 

  39. Long A, Park JH, Klimova N, Fowler C, Loane DJ, Kristian T (2017) CD38 knockout mice show significant protection against ischemic brain damage despite high level poly-ADP-ribosylation. Neurochem Res 42:283–293

    Article  CAS  PubMed  Google Scholar 

  40. Chini CCS, Tarrago MG, Chini EN (2017) NAD and the aging process: role in life, death and everything in between. Mol Cell Endocrinol 455:62–74

    Article  CAS  PubMed  Google Scholar 

  41. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J (2015) SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348:453–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (2017) The SARM1 toll/interleukin-1 receptor domain possesses intrinsic NAD(+) cleavage activity that promotes pathological axonal degeneration. Neuron 93:1334–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. O’Neill LA, Fitzgerald KA, Bowie AG (2003) The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 24:286–290

    Article  PubMed  CAS  Google Scholar 

  44. Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13:539–550

    Article  CAS  PubMed  Google Scholar 

  45. Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23

    Article  CAS  PubMed  Google Scholar 

  46. Marmorstein R, Trievel RC (2009) Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta 1789:58–68

    Article  CAS  PubMed  Google Scholar 

  47. Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1–13

    Article  CAS  PubMed  Google Scholar 

  48. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13:225–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jesko H, Wencel P, Strosznajder RP, Strosznajder JB (2016) Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res 42:876–890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Morris KC, Lin HW, Thompson JW, Perez-Pinzon MA (2011) Pathways for ischemic cytoprotection: role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J Cereb Blood Flow Metab 31:1003–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. He W, Newman JC, Wang MZ, Ho L, Verdin E (2012) Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol Metab 23:467–476

    Article  CAS  PubMed  Google Scholar 

  52. Hirschey MD, Shimazu T, Huang JY, Schwer B, Verdin E (2011) SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harb Symp Quant Biol 76:267–277

    Article  CAS  PubMed  Google Scholar 

  53. Collins PB, Chaykin S (1972) The management of nicotinamide and nicotinic acid in the mouse. J Biol Chem 247:778–783

    CAS  PubMed  Google Scholar 

  54. Magni G, Amici A, Emanuelli M, Raffaelli N, Ruggieri S (1999) Enzymology of NAD + synthesis. Adv Enzymol Relat Areas Mol Biol 73:135–182, xi

    CAS  PubMed  Google Scholar 

  55. Klaidman LK, Mukherjee SK, Hutchin TP, Adams JD (1996) Nicotinamide as a precursor for NAD + prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide. Neurosci Lett 206:5–8

    Article  CAS  PubMed  Google Scholar 

  56. Knip M, Douek IF, Moore WP, Gillmor HA, McLean AE, Bingley PJ, Gale EA, European Nicotinamide Diabetes Intervention Trial G (2000) Safety of high-dose nicotinamide: a review. Diabetologia 43:1337–1345

    Article  CAS  PubMed  Google Scholar 

  57. Yang J, Klaidman LK, Chang ML, Kem S, Sugawara T, Chan P, Adams JD (2002) Nicotinamide therapy protects against both necrosis and apoptosis in a stroke model. Pharmacol Biochem Behav 73:901–910

    Article  CAS  PubMed  Google Scholar 

  58. Hoane MR, Gilbert DR, Holland MA, Pierce JL (2006) Nicotinamide reduces acute cortical neuronal death and edema in the traumatically injured brain. Neurosci Lett 408:35–39

    Article  CAS  PubMed  Google Scholar 

  59. Spector R (1979) Niacin and niacinamide transport in the central nervous system. In vivo studies. J Neurochem 33:895–904

    Article  CAS  PubMed  Google Scholar 

  60. Banasik M, Komura H, Shimoyama M, Ueda K (1992) Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase. J Biol Chem 267:1569–1575

    CAS  PubMed  Google Scholar 

  61. Klaidman LK, Mukherjee SK, Adams JD Jr (2001) Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide. Biochim Biophys Acta 1525:136–148

    Article  CAS  PubMed  Google Scholar 

  62. Chong ZZ, Lin SH, Maiese K (2002) Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. J Vasc Res 39:131–147

    Article  CAS  PubMed  Google Scholar 

  63. Ungerstedt JS, Blomback M, Soderstrom T (2003) Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol 131:48–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mukherjee SK, Klaidman LK, Yasharel R, Adams JD Jr (1997) Increased brain NAD prevents neuronal apoptosis in vivo. Eur J Pharmacol 330:27–34

    Article  CAS  PubMed  Google Scholar 

  65. Yoshino J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14:528–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Klimova N, Kristian T (2019) Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3 dependent mechanism in male mice. J Neurosci Res (in press)

  67. Yoshino J, Baur JA, Imai SI (2018) NAD(+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27:513–528

    Article  CAS  PubMed  Google Scholar 

  68. Grozio A, Sociali G, Sturla L, Caffa I, Soncini D, Salis A, Raffaelli N, De Flora A, Nencioni A, Bruzzone S (2013) CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J Biol Chem 288:25938–25949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nikiforov A, Dolle C, Niere M, Ziegler M (2011) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C (2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 7:12948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Canto C (2016) NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun 7:13103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang X, Hu X, Yang Y, Takata T, Sakurai T (2016) Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 1643:1–9

    Article  CAS  PubMed  Google Scholar 

  73. Yao Z, Yang W, Gao Z, Jia P (2017) Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci Lett 647:133–140

    Article  CAS  PubMed  Google Scholar 

  74. Wang P, Xu TY, Guan YF, Tian WW, Viollet B, Rui YC, Zhai QW, Su DF, Miao CY (2011) Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Ann Neurol 69:360–374

    Article  CAS  PubMed  Google Scholar 

  75. Zhao Y, Guan YF, Zhou XM, Li GQ, Li ZY, Zhou CC, Wang P, Miao CY (2015) Regenerative neurogenesis after ischemic stroke promoted by nicotinamide phosphoribosyltransferase-nicotinamide adenine dinucleotide cascade. Stroke 46:1966–1974

    Article  CAS  PubMed  Google Scholar 

  76. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown R, Janeckova L, Vargas ME, Worrell LA, Loreto A, Tickle J, Patrick J, Webster JR, Marangoni M, Carpi FM, Pucciarelli S, Rossi F, Meng W, Sagasti A, Ribchester RR, Magni G, Coleman MP, Conforti L (2014) A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ 22:731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Girbovan C, Morin L, Plamondon H (2012) Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia. Behav Pharmacol 23:1–13

    Article  CAS  PubMed  Google Scholar 

  79. Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 159:993–1002

    Article  CAS  PubMed  Google Scholar 

  80. Raval AP, Dave KR, Perez-Pinzon MA (2006) Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 26:1141–1147

    Article  CAS  PubMed  Google Scholar 

  81. Yin J, Han P, Tang Z, Liu Q, Shi J (2015) Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. J Cereb Blood Flow Metab 35:1783–1789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Araki T, Sasaki Y, Milbrandt J (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305:1010–1013

    Article  CAS  PubMed  Google Scholar 

  83. Zhai RG, Zhang F, Hiesinger PR, Cao Y, Haueter CM, Bellen HJ (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452:887–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC Jr, Suthammarak W, Gong G, Sedensky MM, Morgan PG, Wang W, Tian R (2013) Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, Edgar JS, Goo YA, Goodlett DR, Bruce JE, Tian R (2016) Normalization of NAD + redox balance as a therapy for heart failure. Circulation 134:883–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Martin AS, Abraham DM, Hershberger KA, Bhatt DP, Mao L, Cui H, Liu J, Liu X, Muehlbauer MJ, Grimsrud PA, Locasale JW, Payne RM, Hirschey MD (2017) Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2:93885

    Article  PubMed  Google Scholar 

  87. Nadtochiy SM, Wang YT, Nehrke K, Munger J, Brookes PS (2018) Cardioprotection by nicotinamide mononucleotide (NMN): involvement of glycolysis and acidic pH. J Mol Cell Cardiol 121:155–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Camacho-Pereira J, Tarrago MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23:1127–1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Imai S (2009) The NAD World: a new systemic regulatory network for metabolism and aging–Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys 53:65–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ramsey KM, Mills KF, Satoh A, Imai S (2008) Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7:78–88

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The project described was supported by Award Number I01BX000917 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development to TK.

Author information

Authors and Affiliations

  1. Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA

    Tibor Kristian

  2. Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, 685 West Baltimore Street, MSTF 534, Baltimore, MD, 21201, USA

    Nina Klimova & Tibor Kristian

Authors
  1. Nina Klimova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tibor Kristian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tibor Kristian.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Special issue in honor of Prof Vera Adam-Vizi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klimova, N., Kristian, T. Multi-targeted Effect of Nicotinamide Mononucleotide on Brain Bioenergetic Metabolism. Neurochem Res 44, 2280–2287 (2019). https://doi.org/10.1007/s11064-019-02729-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02729-0

Keywords

Search

Navigation