Skip to main content

Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models


Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase that regulates longevity and enhances mitochondrial metabolism. Both activation and inhibition of SIRT1 were previously shown to ameliorate neuropathological mechanisms in Huntington’s disease (HD), a neurodegenerative disease that selectively affects the striatum and cortex and is commonly linked to mitochondrial dysfunction. Thus, in this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models, namely striatal and cortical neurons isolated from YAC128 transgenic mice embryos, HD human lymphoblasts, and an in vivo HD model. HD cell models displayed a deregulation in mitochondrial membrane potential and respiration, implicating a decline in mitochondrial function. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Tanner KG, Landry J, Sternglanz R, Denu JM (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc Natl Acad Sci U S A 97:14178–14182. doi:10.1073/pnas.250422697

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Choudhary C, Weinert BT, Nishida Y, et al. (2014) The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15:536–550. doi:10.1038/nrm3841

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 27:2803–2820. doi:10.1111/j.1460-9568.2008.06310.x

    Article  PubMed  Google Scholar 

  4. 4.

    Naia L, Ribeiro MJ, Rego AC (2011) Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q. Rev Neurosci 23:13–28

    PubMed  Google Scholar 

  5. 5.

    Ferreira IL, Cunha-Oliveira T, Nascimento MV, et al. (2011) Bioenergetic dysfunction in Huntington’s disease human cybrids. Exp Neurol 231:127–134. doi:10.1016/j.expneurol.2011.05.024

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Silva AC, Almeida S, Laço M, et al. (2013) Mitochondrial respiratory chain complex activity and bioenergetic alterations in human platelets derived from pre-symptomatic and symptomatic huntington’s disease carriers. Mitochondrion 13:801–809. doi:10.1016/j.mito.2013.05.006

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Naia L, Ferreira IL, Cunha-Oliveira T, et al. (2015) Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s disease human lymphoblasts. Mol Neurobiol 51:331–348. doi:10.1007/s12035-014-8735-4

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Parker JA, Arango M, Abderrahmane S, et al. (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37:349–350. doi:10.1038/ng1534

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Pallos J, Bodai L, Lukacsovich T, et al. (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3767–3775. doi:10.1093/hmg/ddn273

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Naia L, Rego AC (2015) Sirtuins: double players in Huntington’s disease. Biochim Biophys Acta - Mol Basis Dis 1852:2183–2194. doi:10.1016/j.bbadis.2015.07.003

    CAS  Article  Google Scholar 

  11. 11.

    Jiang M, Wang J, Fu J, et al. (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158. doi:10.1038/nm.2558

    CAS  Article  Google Scholar 

  12. 12.

    Tulino R, Benjamin AC, Jolinon N, et al. (2016) SIRT1 activity is linked to its brain region-specific phosphorylation and is impaired in Huntington’s disease mice. PLoS One 11:e0145425. doi:10.1371/journal.pone.0145425

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ho DJ, Calingasan NY, Wille E, et al. (2010) Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol 225:74–84. doi:10.1016/j.expneurol.2010.05.006

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Price NL, Gomes AP, Ling AJY, et al. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690. doi:10.1016/j.cmet.2012.04.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Hubbard BP, Gomes AP, Dai H, et al. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216–1219. doi:10.1126/science.1231097

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Borra MT, Smith BC, Denu JM (2005) Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280:17187–17195. doi:10.1074/jbc.M501250200

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Howitz K, Bitterman J, Cohen H (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196. doi:10.1038/nature01965.1

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Lagouge M, Argmann C, Gerhart-Hines Z, et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122. doi:10.1016/j.cell.2006.11.013

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Pearson KJ, Baur JA, Lewis KN, et al. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168. doi:10.1016/j.cmet.2008.06.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 278:50985–50998. doi:10.1074/jbc.M306552200

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Scholz C, Weinert BT, Wagner SA, et al. (2015) Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat Biotech 33:415–423. doi:10.1038/nbt.3130

    CAS  Article  Google Scholar 

  22. 22.

    Hathorn T, Snyder-Keller A, Messer A (2011) Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis 41:43–50. doi:10.1016/j.nbd.2010.08.017

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ghosh S, Feany MB (2004) Comparison of pathways controlling toxicity in the eye and brain in drosophila models of human neurodegenerative diseases. Hum Mol Genet 13:2011–2018. doi:10.1093/hmg/ddh214

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Schmeisser K, Mansfeld J, Kuhlow D, et al. (2013) Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat Chem Biol 9:693–700. doi:10.1038/nchembio.1352

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Naia L, Ribeiro M, Rodrigues J, et al. (2016) Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides:1–9. doi:10.1016/j.npep.2016.01.009

  26. 26.

    Slow EJ, van Raamsdonk J, Rogers D, et al. (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12:1555–1567. doi:10.1093/hmg/ddg169

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Berta GN, Salamone P, Sprio AE, et al. (2010) Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch by topical application of resveratrol complexed with 2-hydroxypropyl-beta-cyclodextrin. Oral Oncol 46:42–48. doi:10.1016/j.oraloncology.2009.10.007

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Tiwari G, Tiwari R, Rai AK (2010) Cyclodextrins in delivery systems: applications. J Pharm Bioallied Sci 2:72–79. doi:10.4103/0975-7406.67003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Venegas V, Halberg MC (2012) Measurement of mitochondrial DNA copy number. Methods Mol Biol 837:327–335. doi:10.1007/978-1-61779-504-6_22

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Scaduto RC, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469–477. doi:10.1016/S0006-3495(99)77214-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Vaquero A, Scher M, Lee D, et al. (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16:93–105. doi:10.1016/j.molcel.2004.08.031

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Pruitt K, Zinn RL, Ohm JE, et al. (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2:0344–0352. doi:10.1371/journal.pgen.0020040

    CAS  Article  Google Scholar 

  33. 33.

    Nakahata Y, Kaluzova M, Grimaldi B, et al. (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340. doi:10.1016/j.cell.2008.07.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Masri S, Patel VR, Eckel-Mahan KL, et al. (2013) Circadian acetylome reveals regulation of mitochondrial metabolic pathways. Proc Natl Acad Sci 110:3339–3344. doi:10.1073/pnas.1217632110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Sassone J, Colciago C, Cislaghi G, et al. (2009) Huntington’s disease: the current state of research with peripheral tissues. Exp Neurol 219:385–397. doi:10.1016/j.expneurol.2009.05.012

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Noriega LG, Feige JN, Canto C, et al. (2011) CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep 12:1069–1076. doi:10.1038/embor.2011.151

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cui L, Jeong H, Borovecki F, et al. (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69. doi:10.1016/j.cell.2006.09.015

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Taherzadeh-Fard E, Saft C, Akkad DA, et al. (2011) PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 6:32. doi:10.1186/1750-1326-6-32

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Weydt P, Pineda VV, Torrence AE, et al. (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4:349–362. doi:10.1016/j.cmet.2006.10.004

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Ngo HB, Lovely GA, Phillips R, Chan DC (2014) Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat Commun 5:3077. doi:10.1038/ncomms4077

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Van Raamsdonk JM, Pearson J, Slow EJ, et al. (2005) Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. J Neurosci 25:4169–4180. doi:10.1523/JNEUROSCI.0590-05.2005

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Brandt J, Strauss ME, Larus J, et al. (1984) Clinical correlates of dementia and disability in Huntington’s disease. J Clin Neuropsychol 6:401–412. doi:10.1080/01688638408401231

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Shirendeb U, Reddy AP, Manczak M, et al. (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet 20:1438–1455. doi:10.1093/hmg/ddr024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Jiang M, Zheng J, Peng Q, et al. (2014) Sirtuin 1 activator SRT2104 protects Huntington’s disease mice. Ann Clin Transl Neurol 1:1047–1052. doi:10.1002/acn3.135

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Pacholec M, Bleasdale JE, Chrunyk B, et al. (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285:8340–8351. doi:10.1074/jbc.M109.088682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506. doi:10.1038/nrd2060

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Hankes LV, Coenen HH, Rota E, et al. (1991) Effect of Huntington’s and Alzheimer’s diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier. AdvExpMedBiol 294:675–678

    CAS  Google Scholar 

  48. 48.

    Baur JA, Pearson KJ, Price NL, et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. doi:10.1038/nature05354

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Panov AV, Gutekunst CA, Leavitt BR, et al. (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736. doi:10.1038/nn884

    CAS  PubMed  Google Scholar 

  50. 50.

    Yano H, Baranov SV, Baranova OV, et al. (2014) Inhibition of mitochondrial protein import by mutant huntingtin. Nat Neurosci 17:822–831. doi:10.1038/nn.3721

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Cunha-Oliveira T, Lusa I, Cristina A (2012) Consequences of mitochondrial dysfunction in Huntington’s disease and protection via phosphorylation pathways. Huntington’s Dis - Core Concepts Curr Adv. doi:10.5772/32728

    Google Scholar 

  52. 52.

    Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278. doi:10.1016/j.bbamcr.2010.09.019

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Lopes costa A, Le bachelier C, Mathieu L, et al. (2014) Beneficial effects of resveratrol on respiratory chain defects in patients’ fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet 23:2106–2119. doi:10.1093/hmg/ddt603

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Bitterman KJ, Anderson RM, Cohen HY, et al. (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem 277:45099–45107. doi:10.1074/jbc.M205670200

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Sauve AA (2008) NAD+ and vitamin B 3 : from metabolism to therapies. J Pharmacol Exp Ther 324:883–893. doi:10.1124/

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Klaidman L, Morales M, Kem S, et al. (2003) Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology 69:150–157. doi:10.1159/000072668

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Chong ZZ, Lin SH, Li F, Maiese K (2005) The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated “anti-apoptotic” pathways. Curr Neurovasc Res 2:271–285. doi:10.2174/156720205774322584

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Liu D, Gharavi R, Pitta M, et al. (2009) Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by sirt1 may endanger energetically compromised neurons. Neruomol Med 11:28–42. doi:10.1007/s12017-009-8058-1

    CAS  Article  Google Scholar 

  59. 59.

    Vang O, Ahmad N, Baile CA, et al. (2011) What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. doi:10.1371/journal.pone.0019881

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to A. Cristina Rego.

Ethics declarations

Animals’ maintenance and procedures were performed in accordance with the protocols approved by the Ethical Commission from the Faculty of Medicine, University of Coimbra (FMUC). Euthanasia by halothane or isoflurane anesthesia and decapitation was performed according to EU guideline 86/609/EEC and Annex II of Portuguese decree-law No. 113/2013.


This work was supported by “Fundo Europeu de Desenvolvimento Regional” (FEDER) funds through the “Programa Operacional Factores de Competitividade” (COMPETE), projects reference PEst-C/SAU/LA0001/2013–2014 and UID/NEU/04539/2013; and by national funds through “Fundação para a Ciência e a Tecnologia” (FCT), projects reference PTDC/SAU-FCF/108056/2008, EXPL/BIM-MEC/2220/2013, and Mantero Belard Neuroscience prize 2013, supported by Santa Casa da Misericórdia de Lisboa (SCML), Portugal. L.N. was supported by the FCT PhD fellowship SFRH/BD/86655/2012; T.R.R. and M.N.L. were supported by the FCT postdoctoral fellowships SFRH/BPD/44246/2008 and SFRH/BPD/91811/2012, respectively; and A.M.O. was supported by the FCT technician fellowship under the research project EXPL/BIM-MEC/2220/2013, cofinanced by Programa Operacional Potencial Humano (POPH), QREN, and European Union.

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM. 1

(PDF 2487 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Naia, L., Rosenstock, T.R., Oliveira, A.M. et al. Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models. Mol Neurobiol 54, 5385–5399 (2017).

Download citation


  • Huntington’s disease
  • Lysine (de)acetylation
  • Mitochondria
  • Nicotinamide
  • Resveratrol
  • Sirtuins