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Sulforaphane Promotes Mitochondrial Protection in SH-SY5Y Cells Exposed to Hydrogen Peroxide by an Nrf2-Dependent Mechanism

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Abstract

Sulforaphane (SFN; C6H11NOS2) is an isothiocyanate found in cruciferous vegetables, such as broccoli, kale, and radish. SFN exhibits antioxidant, anti-apoptotic, anti-tumor, and anti-inflammatory activities in different cell types. However, it was not previously demonstrated whether and how this natural compound would exert mitochondrial protection experimentally. Therefore, we investigated here the effects of a pretreatment (for 30 min) with SFN at 5 μM on mitochondria obtained from human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide (H2O2) at 300 μM for 24 h. We found that SFN prevented loss of viability in H2O2-treated SH-SY5Y cells. Furthermore, SFN decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes of H2O2-exposed cells. Importantly, SFN enhanced the levels of both cellular and mitochondrial glutathione (GSH). SFN also suppressed the H2O2-mediated inhibition of mitochondrial components involved in the maintenance of the bioenergetics state, such as aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase, as well as complexes I and V. Consequently, SFN prevented the decline induced by H2O2 on the levels of ATP in SH-SY5Y cells. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by using small interfering RNA (siRNA) abolished the mitochondrial and cellular protection elicited by SFN. Therefore, SFN abrogated the H2O2-induced mitochondrial impairment by an Nrf2-dependent manner.

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References

  1. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R560

    Article  CAS  PubMed  Google Scholar 

  2. Bornhövd C, Vogel F, Neupert W, Reichert AS (2006) Mitochondrial membrane potential is dependent on the oligomeric state of F1F0-ATP synthase supracomplexes. J Biol Chem 281:13990–13998

    Article  PubMed  Google Scholar 

  3. Van Bergen NJ, Blake RE, Crowston JG, Trounce IA (2014) Oxidative phosphorylation measurement in cell lines and tissues. Mitochondrion 15:24–33. doi:10.1016/j.mito.2014.03.003

    Article  PubMed  Google Scholar 

  4. Fernández-Checa JC, García-Ruiz C, Colell A, Morales A, Marí M, Miranda M, Ardite E (1998) Oxidative stress: role of mitochondria and protection by glutathione. Biofactors 8:7–11

    Article  PubMed  Google Scholar 

  5. Tretter L, Adam-Vizi V (2005) Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond Ser B Biol Sci 360:2335–2345

    Article  CAS  Google Scholar 

  6. Quijano C, Trujillo M, Castro L, Trostchansky A (2016) Interplay between oxidant species and energy metabolism. Redox Biol 8:28–42. doi:10.1016/j.redox.2015.11.010

    Article  CAS  PubMed  Google Scholar 

  7. Gibson GE, Blass JP, Beal MF, Bunik V (2005) The alpha-ketoglutarate-dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration. Mol Neurobiol 31:43–63

    Article  CAS  PubMed  Google Scholar 

  8. Adam-Vizi V, Tretter L (2013) The role of mitochondrial dehydrogenases in the generation of oxidative stress. Neurochem Int 62:757–763. doi:10.1016/j.neuint.2013.01.012

    Article  CAS  PubMed  Google Scholar 

  9. Kasote DM, Hegde MV, Katyare SS (2013) Mitochondrial dysfunction in psychiatric and neurological diseases: cause(s), consequence(s), and implications of antioxidant therapy. Biofactors 39:392–406. doi:10.1002/biof.1093

    Article  CAS  PubMed  Google Scholar 

  10. de Oliveira MR, Jardim FR (2016) Cocaine and mitochondria-related signaling in the brain: a mechanistic view and future directions. Neurochem Int 92:58–66. doi:10.1016/j.neuint.2015.12.006

    Article  PubMed  Google Scholar 

  11. de Oliveira MR (2016) Fluoxetine and the mitochondria: a review of the toxicological aspects. Toxicol Lett 258:185–191. doi:10.1016/j.toxlet.2016.07.001

    Article  PubMed  Google Scholar 

  12. Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu Rev Biochem IN PRESS doi. doi:10.1146/annurev-biochem-061516-045037

  13. Sies H (1993) Strategies of antioxidant defense. Eur J Biochem 215:213–219

    Article  CAS  PubMed  Google Scholar 

  14. Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1–14

    Article  CAS  PubMed  Google Scholar 

  15. Brigelius-Flohé R, Kipp A (2009) Glutathione peroxidases in different stages of carcinogenesis. Biochim Biophys Acta 1790:1555–1568. doi:10.1016/j.bbagen.2009.03.006

    Article  PubMed  Google Scholar 

  16. Brigelius-Flohé R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta 1830:3289–3303. doi:10.1016/j.bbagen.2012.11.020

    Article  PubMed  Google Scholar 

  17. Salinas AE, Wong MG (1999) Glutathione S-transferases—a review. Curr Med Chem 6:279–309

    CAS  PubMed  Google Scholar 

  18. Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830:3143–3153. doi:10.1016/j.bbagen.2012.09.008

    Article  CAS  PubMed  Google Scholar 

  19. Marí M, Morales A, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC (2013) Mitochondrial glutathione: features, regulation and role in disease. Biochim Biophys Acta 1830:3317–3328. doi:10.1016/j.bbagen.2012.10.018

    Article  PubMed  Google Scholar 

  20. Morris G, Anderson G, Dean O, Berk M, Galecki P, Martin-Subero M, Maes M (2014) The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol 50:1059–1084. doi:10.1007/s12035-014-8705-x

    Article  CAS  PubMed  Google Scholar 

  21. Perry TL, Godin DV, Hansen S (1982) Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 33:305–310

    Article  CAS  PubMed  Google Scholar 

  22. Adams JD Jr, Klaidman LK, Odunze IN, Shen HC, Miller CA (1991) Alzheimer’s and Parkinson’s disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. Mol Chem Neuropathol 14:213–226

    Article  CAS  PubMed  Google Scholar 

  23. Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355

    Article  CAS  PubMed  Google Scholar 

  24. Liddell JR, White AR (2017) Nexus between mitochondrial function, iron, copper and glutathione in Parkinson’s disease. Neurochem Int IN PRESS doi. doi:10.1016/j.neuint.2017.05.016

  25. Fernández-Checa JC, Kaplowitz N, García-Ruiz C, Colell A, Miranda M, Marí M, Ardite E, Morales A (1997) GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Phys 273:G7–G17

    Article  Google Scholar 

  26. de Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z, Nabavi SM (2016) Resveratrol and the mitochondria: from triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochim Biophys Acta 1860:727–745. doi:10.1016/j.bbagen.2016.01.017

    Article  PubMed  Google Scholar 

  27. de Oliveira MR, Jardim FR, Setzer WN, Nabavi SM, Nabavi SF (2016) Curcumin, mitochondrial biogenesis, and mitophagy: exploring recent data and indicating future needs. Biotechnol Adv 34:813–826. doi:10.1016/j.biotechadv.2016.04.004

    Article  PubMed  Google Scholar 

  28. de Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF (2016) Quercetin and the mitochondria: a mechanistic view. Biotechnol Adv 34:532–549. doi:10.1016/j.biotechadv.2015.12.014

    Article  PubMed  Google Scholar 

  29. Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC, de Oliveira MR (2017) Resveratrol and brain mitochondria: a review. Mol Neurobiol IN PRESS doi. doi:10.1007/s12035-017-0448-z

  30. Baird L, Swift S, Llères D, Dinkova-Kostova AT (2014) Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv 32:1133–1144. doi:10.1016/j.biotechadv.2014.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dinkova-Kostova AT, Abramov AY (2015) The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 88:179–188. doi:10.1016/j.freeradbiomed.2015.04.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou R, Lin J, Wu D (2014) Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochim Biophys Acta 1840:209–218. doi:10.1016/j.bbagen.2013.09.018

    Article  CAS  PubMed  Google Scholar 

  33. de Oliveira MR, Ferreira GC, Schuck PF (2016) Protective effect of carnosic acid against paraquat-induced redox impairment and mitochondrial dysfunction in SH-SY5Y cells: Role for PI3K/Akt/Nrf2 pathway. Toxicol in Vitro 32:41–54. doi:10.1016/j.tiv.2015.12.005

    Article  PubMed  Google Scholar 

  34. Copple IM, Dinkova-Kostova AT, Kensler TW, Liby KT, Wigley WC (2017) NRF2 as an emerging therapeutic target. Oxidative Med Cell Longev 2017:8165458. doi:10.1155/2017/8165458

    Article  Google Scholar 

  35. de Oliveira MR, da Costa FG, Peres A, Bosco SM (2017) Carnosic acid suppresses the H2O2-induced mitochondria-related bioenergetics disturbances and redox impairment in SH-SY5Y cells: role for Nrf2. Mol Neurobiol IN PRESS doi. doi:10.1007/s12035-016-0372-7

  36. de Oliveira MR, da Costa FG, Brasil FB, Peres A (2017) Pinocembrin suppresses H2O2-induced mitochondrial dysfunction by a mechanism dependent on the Nrf2/HO-1 Axis in SH-SY5Y cells. Mol Neurobiol IN PRESS doi. doi:10.1007/s12035-016-0380-7

  37. Atamna H, Mackey J, Dhahbi JM (2012) Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction. Biofactors 38:158–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S, Cheah I, Halliwell B (2013) Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv 31:563–592. doi:10.1016/j.biotechadv.2012.09.005

    Article  CAS  PubMed  Google Scholar 

  39. Picard M, Wallace DC, Burelle Y (2016) The rise of mitochondria in medicine. Mitochondrion 30:105–116. doi:10.1016/j.mito.2016.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. de Oliveira MR (2016) Evidence for genistein as a mitochondriotropic molecule. Mitochondrion 29:35–44. doi:10.1016/j.mito.2016.05.005

    Article  PubMed  Google Scholar 

  41. Amjad AI, Parikh RA, Appleman LJ, Hahm ER, Singh K, Singh SV (2015) Broccoli-derived sulforaphane and chemoprevention of prostate cancer: from bench to bedside. Curr Pharmacol Rep 1:382–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Houghton CA, Fassett RG, Coombes JS (2016) Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician's expectation be matched by the reality? Oxidative Med Cell Longev 2016:7857186. doi:10.1155/2016/7857186

    Article  Google Scholar 

  43. Brown KK, Hampton MB (2011) Biological targets of isothiocyanates. Biochim Biophys Acta 1810:888–894. doi:10.1016/j.bbagen.2011.06.004

    Article  CAS  PubMed  Google Scholar 

  44. Bai Y, Wang X, Zhao S, Ma C, Cui J, Zheng Y (2015) Sulforaphane protects against cardiovascular disease via Nrf2 activation. Oxidative Med Cell Longev 2015:407580. doi:10.1155/2015/407580

    Article  Google Scholar 

  45. Denzer I, Münch G, Friedland K (2016) Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds. Pharmacol Res 103:80–94. doi:10.1016/j.phrs.2015.11.019

    Article  CAS  PubMed  Google Scholar 

  46. Naoi M, Maruyama W, Shamoto-Nagai M, Yi H, Akao Y, Tanaka M (2005) Oxidative stress in mitochondria: decision to survival and death of neurons in neurodegenerative disorders. Mol Neurobiol 31:81–93

    Article  CAS  PubMed  Google Scholar 

  47. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  48. LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231

    Article  CAS  PubMed  Google Scholar 

  49. de Oliveira MR, da Rocha RF, Moreira JC (2012) Increased susceptibility of mitochondria isolated from frontal cortex and hippocampus of vitamin A-treated rats to non-aggregated amyloid-β peptides 1-40 and 1-42. Acta Neuropsychiatr 24:101–108. doi:10.1111/j.1601-5215.2011.00588.x

    Article  PubMed  Google Scholar 

  50. Wang K, Zhu L, Zhu X, Zhang K, Huang B, Zhang J, Zhang Y, Zhu L et al (2014) Protective effect of paeoniflorin on Aβ25-35-induced SH-SY5Y cell injury by preventing mitochondrial dysfunction. Cell Mol Neurobiol 34:227–234. doi:10.1007/s10571-013-0006-9

  51. Poderoso JJ, Carreras MC, Lisdero C, Riobó N, Schöpfer F, Boveris A (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328:85–92

    Article  CAS  PubMed  Google Scholar 

  52. de Oliveira MR, da Rocha RF, Stertz L, Fries GR, de Oliveira DL, Kapczinski F, Moreira JC (2011) Total and mitochondrial nitrosative stress, decreased brain-derived neurotrophic factor (BDNF) levels and glutamate uptake, and evidence of endoplasmic reticulum stress in the hippocampus of vitamin A-treated rats. Neurochem Res 36:506–517. doi:10.1007/s11064-010-0372-3

    Article  PubMed  Google Scholar 

  53. de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM (2015) Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact 242:396–406. doi:10.1016/j.cbi.2015.11.003

    Article  PubMed  Google Scholar 

  54. de Oliveira MR, Schuck PF, Bosco SM (2016) Tanshinone I induces mitochondrial protection through an Nrf2-dependent mechanism in Paraquat-treated human neuroblastoma SH-SY5Y cells. Mol Neurobiol IN PRESS doi. doi:10.1007/s12035-016-0009-x

  55. Tarozzi A, Morroni F, Merlicco A, Hrelia S, Angeloni C, Cantelli-Forti G, Hrelia P (2009) Sulforaphane as an inducer of glutathione prevents oxidative stress-induced cell death in a dopaminergic-like neuroblastoma cell line. J Neurochem 111:1161–1171. doi:10.1111/j.1471-4159.2009.06394.x

    Article  CAS  PubMed  Google Scholar 

  56. Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20:8972–8979

    Article  CAS  PubMed  Google Scholar 

  57. Gibson GE, Kingsbury AE, Xu H, Lindsay JG, Daniel S, Foster OJ, Lees AJ, Blass JP (2003) Deficits in a tricarboxylic acid cycle enzyme in brains from patients with Parkinson’s disease. Neurochem Int 43:129–135

    Article  CAS  PubMed  Google Scholar 

  58. Naseri NN, Xu H, Bonica J, Vonsattel JP, Cortes EP, Park LC, Arjomand J, Gibson GE (2015) Abnormalities in the tricarboxylic acid cycle in Huntington disease and in a Huntington disease mouse model. J Neuropathol Exp Neurol 74:527–537. doi:10.1097/NEN.0000000000000197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sandoval-Acuña C, Ferreira J, Speisky H (2014) Polyphenols and mitochondria: an update on their increasingly emerging ROS-scavenging independent actions. Arch Biochem Biophys 559:75–90. doi:10.1016/j.abb.2014.05.017

    Article  PubMed  Google Scholar 

  60. Holmström KM, Kostov RV, Dinkova-Kostova AT (2016) The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol 1:80–91. doi:10.1016/j.cotox.2016.10.002

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ludtmann MH, Angelova PR, Zhang Y, Abramov AY, Dinkova-Kostova AT (2014) Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J 457:415–424. doi:10.1042/BJ20130863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Holmström KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM, Stanyer L, Yamamoto M et al (2013) Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open 2:761–770. doi:10.1242/bio.20134853

  63. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85

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Acknowledgements

This work was supported by CNPq. FBB receives financial support from the FOPESQ/UFF.

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Authors and Affiliations

  1. Departamento de Química/ICET, Universidade Federal de Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, 2367, CEP 78060-900, Cuiaba, MT, Brazil

    Marcos Roberto de Oliveira

  2. Universidade Federal Fluminense, Rio de Janeiro, RJ, Brazil

    Flávia de Bittencourt Brasil

  3. Instituto de Genética e Bioquímica (INGEB), Universidade Federal de Uberlândia (UFU), Patos de Minas, MG, Brazil

    Cristina Ribas Fürstenau

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  1. Marcos Roberto de Oliveira
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  2. Flávia de Bittencourt Brasil
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  3. Cristina Ribas Fürstenau
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Correspondence to Marcos Roberto de Oliveira.

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de Oliveira, M.R., de Bittencourt Brasil, F. & Fürstenau, C.R. Sulforaphane Promotes Mitochondrial Protection in SH-SY5Y Cells Exposed to Hydrogen Peroxide by an Nrf2-Dependent Mechanism. Mol Neurobiol 55, 4777–4787 (2018). https://doi.org/10.1007/s12035-017-0684-2

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