Abstract
Mitochondrion is the main site of ATP production in animal cells and also orchestrates signaling pathways associated with cell survival and death. Mitochondrial dysfunction has been linked to bioenergetics and redox impairment in human diseases, such as neurodegeneration and cardiovascular disease. Protective agents able to attenuate mitochondrial impairment are of pharmacological interest. Gastrodin (GAS; 4-hydroxybenzyl alcohol 4-O-beta-d-glucoside) is a phenolic glucoside obtained from the Chinese herbal medicine Gastrodia elata Blume and exhibits antioxidant, anti-inflammatory, and antiapoptotic effects in several cell types. GAS is able to cross the blood-brain barrier, reducing the impact of different stressors on the cognition of experimental animals. In the present work, we investigated whether GAS would protect mitochondria of human SH-SY5Y neuroblastoma cells against an exposure to a pro-oxidant agent. The cells were treated with GAS at 25 μM for 30 min before the administration of hydrogen peroxide (H2O2) at 300 μM for an additional 3 or 24 h, depending on the assay. We evaluated both mitochondrial redox state and function parameters and analyzed the mechanism by which GAS protected mitochondria in this experimental model. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor suppressed the GAS-induced mitochondrial protection seen here. Moreover, Nrf2 knockdown abrogated the effects of GAS on cell viability, indicating a potential role for Nrf2 in both mitochondrial and cellular protection promoted by GAS. Further research would be necessary to investigate whether GAS would be able to induce similar effects in in vivo experimental models.
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Ahmed SM, Luo L, Namani A, Wang XJ, Tang X (2017) Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta 1863(2):585–597. https://doi.org/10.1016/j.bbadis.2016.11.005
Anandhan A, Jacome MS, Lei S, Hernandez-Franco P, Pappa A, Panayiotidis MI, Powers R, Franco R (2017) Metabolic dysfunction in Parkinson’s disease: bioenergetics, redox homeostasis and central carbon metabolism. Brain Res Bull 133:12–30. https://doi.org/10.1016/j.brainresbull.2017.03.009
Arnold S (2012) The power of life—cytochrome c oxidase takes center stage in metabolic control, cell signalling and survival. Mitochondrion 12(1):46–56. https://doi.org/10.1016/j.mito.2011.05.003
Broadley SA, Hartl FU (2008) Mitochondrial stress signaling: a pathway unfolds. Trends Cell Biol 18(1):1–4. https://doi.org/10.1016/j.tcb.2007.11.003
Chen WC, Lai YS, Lin SH, Lu KH, Lin YE, Panyod S, Ho CT, Sheen LY (2016) Anti-depressant effects of Gastrodia elata Blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling. J Ethnopharmacol 182:190–199. https://doi.org/10.1016/j.jep.2016.02.001
Chen J, Gu YT, Xie JJ, Wu CC, Xuan J, Guo WJ, Yan YZ, Chen L, Wu YS, Zhang XL, Xiao J, Wang XY (2017a) Gastrodin reduces IL-1β-induced apoptosis, inflammation, and matrix catabolism in osteoarthritis chondrocytes and attenuates rat cartilage degeneration in vivo. Biomed Pharmacother 97:642–651. https://doi.org/10.1016/j.biopha.2017.10.067
Chen L, Liu X, Wang H, Qu M (2017b) Gastrodin attenuates pentylenetetrazole-induced seizures by modulating the mitogen-activated protein kinase-associated inflammatory responses in mice. Neurosci Bull 33(3):264–272. https://doi.org/10.1007/s12264-016-0084-z
Chong SJ, Low IC, Pervaiz S (2014) Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. Mitochondrion 19 Pt A:39–48. https://doi.org/10.1016/j.mito.2014.06.002
Coombes E, Jiang J, Chu XP, Inoue K, Seeds J, Branigan D, Simon RP, Xiong ZG (2011) Pathophysiologically relevant levels of hydrogen peroxide induce glutamate-independent neurodegeneration that involves activation of transient receptor potential melastatin 7 channels. Antioxid Redox Signal 14(10):1815–1827. https://doi.org/10.1089/ars.2010.3549
Costa SL, Silva VD, Dos Santos Souza C, Santos CC, Paris I, Muñoz P, Segura-Aguilar J (2016) Impact of plant-derived flavonoids on neurodegenerative diseases. Neurotox Res 30(1):41–52. https://doi.org/10.1007/s12640-016-9600-1
de Oliveira MR (2015) Vitamin A and retinoids as mitochondrial toxicants. Oxidative Med Cell Longev 2015:140267–140213. https://doi.org/10.1155/2015/140267
de Oliveira MR (2016a) Fluoxetine and the mitochondria: a review of the toxicological aspects. Toxicol Lett 258:185–191. https://doi.org/10.1016/j.toxlet.2016.07.001
de Oliveira MR (2016b) Evidence for genistein as a mitochondriotropic molecule. Mitochondrion 29:35–44. https://doi.org/10.1016/j.mito.2016.05.005
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. https://doi.org/10.1016/j.neuint.2015.12.006
de Oliveira MR, Moreira JC (2007) Acute and chronic vitamin A supplementation at therapeutic doses induces oxidative stress in submitochondrial particles isolated from cerebral cortex and cerebellum of adult rats. Toxicol Lett 173(3):145–150. https://doi.org/10.1016/j.toxlet.2007.07.002
de Oliveira MR, Soares Oliveira MW, Müller Hoff ML, Behr GA, da Rocha RF, Fonseca Moreira JC (2009) Evaluation of redox and bioenergetics states in the liver of vitamin A-treated rats. Eur J Pharmacol 610(1-3):99–105. https://doi.org/10.1016/j.ejphar.2009.03.046
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(3):506–517. https://doi.org/10.1007/s11064-010-0372-3
de Oliveira MR, da Rocha RF, Pasquali MA, Moreira JC (2012) The effects of vitamin A supplementation for 3 months on adult rat nigrostriatal axis: increased monoamine oxidase enzyme activity, mitochondrial redox dysfunction, increased β-amyloid(1-40) peptide and TNF-α contents, and susceptibility of mitochondria to an in vitro H2O2 challenge. Brain Res Bull 87(4-5):432–444. https://doi.org/10.1016/j.brainresbull.2012.01.005
de Oliveira MR, Nabavi SF, Habtemariam S, Erdogan Orhan I, Daglia M, Nabavi SM (2015a) The effects of baicalein and baicalin on mitochondrial function and dynamics: a review. Pharmacol Res 100:296–308. https://doi.org/10.1016/j.phrs.2015.08.021
de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM (2015b) 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. https://doi.org/10.1016/j.cbi.2015.11.003
de Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z, Nabavi SM (2016a) Resveratrol and the mitochondria: from triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochim Biophys Acta 1860(4):727–745. https://doi.org/10.1016/j.bbagen.2016.01.017
de Oliveira MR, Jardim FR, Setzer WN, Nabavi SM, Nabavi SF (2016b) Curcumin, mitochondrial biogenesis, and mitophagy: exploring recent data and indicating future needs. Biotechnol Adv 34(5):813–826. https://doi.org/10.1016/j.biotechadv.2016.04.004
de Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF (2016c) Quercetin and the mitochondria: a mechanistic view. Biotechnol Adv 34(5):532–549. https://doi.org/10.1016/j.biotechadv.2015.12.014
de Oliveira MR, Ferreira GC, Schuck PF (2016d) 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. https://doi.org/10.1016/j.tiv.2015.12.005
de Oliveira MR, Peres A, Ferreira GC, Schuck PF, Bosco SM (2016e) Carnosic acid affords mitochondrial protection in chlorpyrifos-treated Sh-Sy5y cells. Neurotox Res 30(3):367–379. https://doi.org/10.1007/s12640-016-9620-x
de Oliveira MR, da Costa Ferreira G, Peres A, Bosco SM (2017a) Carnosic acid suppresses the H2O2-induced mitochondria-related bioenergetics disturbances and redox impairment in SH-SY5Y cells: role for Nrf2. Mol Neurobiol. https://doi.org/10.1007/s12035-016-0372-7
de Oliveira MR, Schuck PF, Bosco SMD (2017b) Tanshinone I induces mitochondrial protection through an Nrf2-dependent mechanism in paraquat-treated human neuroblastoma SH-SY5Y cells. Mol Neurobiol 54(6):4597–4608. https://doi.org/10.1007/s12035-016-0009-x
de Oliveira MR, Brasil FB, Andrade CMB (2017c) Naringenin attenuates H2O2-induced mitochondrial dysfunction by an Nrf2-dependent mechanism in SH-SY5Y cells. Neurochem Res 42(11):3341–3350. https://doi.org/10.1007/s11064-017-2376-8
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. https://doi.org/10.1080/01926230701320337
Enríquez JA (2016) Supramolecular organization of respiratory complexes. Annu Rev Physiol 78(1):533–561. https://doi.org/10.1146/annurev-physiol-021115-105031
Erpapazoglou Z, Mouton-Liger F, Corti O (2017) From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration. Neurochem Int 109:171–183. https://doi.org/10.1016/j.neuint.2017.03.021
Flippo KH, Strack S (2017) Mitochondrial dynamics in neuronal injury, development and plasticity. J Cell Sci 130(4):671–681. https://doi.org/10.1242/jcs.171017
Green DR, Galluzzi L, Kroemer G (2014) Metabolic control of cell death. Science 345(6203):1250256. https://doi.org/10.1126/science.1250256
Ito YA, Di Polo A (2017) Mitochondrial dynamics, transport, and quality control: a bottleneck for retinal ganglion cell viability in optic neuropathies. Mitochondrion 36:186–192. https://doi.org/10.1016/j.mito.2017.08.014
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. https://doi.org/10.1007/s12035-017-0448-z
Jiang G, Hu Y, Liu L, Cai J, Peng C, Li Q (2014) Gastrodin protects against MPP(+)-induced oxidative stress by up regulates heme oxygenase-1 expression through p38 MAPK/Nrf2 pathway in human dopaminergic cells. Neurochem Int 75:79–88. https://doi.org/10.1016/j.neuint.2014.06.003
Jin YN, Yu YV, Gundemir S, Jo C, Cui M, Tieu K, Johnson GV (2013) Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One 8(3):e57932. https://doi.org/10.1371/journal.pone.0057932
Jin X, Liu Q, Jia L, Li M, Wang X (2015) Pinocembrin attenuates 6-OHDA-induced neuronal cell death through Nrf2/ARE pathway in SH-SY5Y cells. Cell Mol Neurobiol 35(3):323–333. https://doi.org/10.1007/s10571-014-0128-8
Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35(2):211–225. https://doi.org/10.1007/s10545-011-9382-9
Kanaan GN, Harper ME (2017) Cellular redox dysfunction in the development of cardiovascular diseases. Biochim Biophys Acta 1861(11):2822–2829. https://doi.org/10.1016/j.bbagen.2017.07.027
Kim J, Keum YS (2016) NRF2, a key regulator of antioxidants with two faces towards cancer. Oxidative Med Cell Longev 2016:2746457. https://doi.org/10.1155/2016/2746457
Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Cancer Res 71:2260–2275. https://doi.org/10.1158/0008-5472.CAN-10-3007
Klamt F, Roberto de Oliveira M, Moreira JC (2005) Retinol induces permeability transition and cytochrome c release from rat liver mitochondria. Biochim Biophys Acta 1726(1):14–20. https://doi.org/10.1016/j.bbagen.2005.07.016
Koppenhöfer D, Kettenbaum F, Susloparova A, Law JK, Vu XT, Schwab T, Schäfer KH, Ingebrandt S (2015) Neurodegeneration through oxidative stress: monitoring hydrogen peroxide induced apoptosis in primary cells from the subventricular zone of BALB/c mice using field-effect transistors. Biosens Bioelectron 67:490–496. https://doi.org/10.1016/j.bios.2014.09.012
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(2):227–231. https://doi.org/10.1021/tx00026a012
Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH (2016) Gastrodin reversed the traumatic stress-induced depressed-like symptoms in rats. J Nat Med 70(4):749–759. https://doi.org/10.1007/s11418-016-1010-4
Letts JA, Sazanov LA (2017) Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 24(10):800–808. https://doi.org/10.1038/nsmb.3460
Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830(5):3143–3153. https://doi.org/10.1016/j.bbagen.2012.09.008
Ludtmann MH, Angelova PR, Zhang Y, Abramov AY, Dinkova-Kostova AT (2014) Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J 457(3):415–424. https://doi.org/10.1042/BJ20130863
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53(1):401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2):55–63. https://doi.org/10.1016/0022-1759(83)90303-4
Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295. https://doi.org/10.1074/jbc.R900010200
Oliveira MR (2015) The neurotoxic effects of vitamin A and retinoids. An Acad Bras Cienc 87(2 suppl):1361–1373. https://doi.org/10.1590/0001-3765201520140677
Ott M, Zhivotovsky B, Orrenius S (2007) Role of cardiolipin in cytochrome c release from mitochondria. Cell Death Differ 14(7):1243–1247. https://doi.org/10.1038/sj.cdd.4402135
Peixoto PM, Dejean LM, Kinnally KW (2012) The therapeutic potential of mitochondrial channels in cancer, ischemia-reperfusion injury, and neurodegeneration. Mitochondrion 12(1):14–23. https://doi.org/10.1016/j.mito.2011.03.003
Peng Z, Wang H, Zhang R, Chen Y, Xue F, Nie H, Chen Y, Wu D, Wang Y, Wang H, Tan Q (2013) Gastrodin ameliorates anxiety-like behaviors and inhibits IL-1beta level and p38 MAPK phosphorylation of hippocampus in the rat model of posttraumatic stress disorder. Physiol Res 62(5):537–545
Peng Z, Wang S, Chen G, Cai M, Liu R, Deng J, Liu J, Zhang T, Tan Q, Hai C (2015) Gastrodin alleviates cerebral ischemic damage in mice by improving anti-oxidant and anti-inflammation activities and inhibiting apoptosis pathway. Neurochem Res 40(4):661–673. https://doi.org/10.1007/s11064-015-1513-5
Picard M, Wallace DC, Burelle Y (2016) The rise of mitochondria in medicine. Mitochondrion 30:105–116. https://doi.org/10.1016/j.mito.2016.07.003
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(1):85–92. https://doi.org/10.1006/abbi.1996.0146
Quesada A, Ogi J, Schultz J, Handforth A (2011) C-terminal mechano-growth factor induces heme oxygenase-1-mediated neuroprotection of SH-SY5Y cells via the protein kinase Cϵ/Nrf2 pathway. J Neurosci Res 89(3):394–405. https://doi.org/10.1002/jnr.22543
Robinson JB Jr, Srere PA (1985) Organization of Krebs tricarboxylic acid cycle enzymes in mitochondria. J Biol Chem 260(19):10800–10805
Sachdeva MM, Cano M, Handa JT (2014) Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res 119:111–114. https://doi.org/10.1016/j.exer.2013.10.024
Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu Rev Biochem 86(1):715–748. https://doi.org/10.1146/annurev-biochem-061516-045037
Tocchi A, Quarles EK, Basisty N, Gitari L, Rabinovitch PS (2015) Mitochondrial dysfunction in cardiac aging. Biochim Biophys Acta 1847(11):1424–1433. https://doi.org/10.1016/j.bbabio.2015.07.009
Wang Q, Chen G, Zeng S (2008) Distribution and metabolism of gastrodin in rat brain. J Pharm Biomed Anal 46(2):399–404. https://doi.org/10.1016/j.jpba.2007.10.017
Wang K, Zhu L, Zhu X, Zhang K, Huang B, Zhang J, Zhang Y, Zhu L, Zhou B, Zhou F (2014) Protective effect of paeoniflorin on Aβ25-35-induced SH-SY5Y cell injury by preventing mitochondrial dysfunction. Cell Mol Neurobiol 34(2):227–234. https://doi.org/10.1007/s10571-013-0006-9
Witte ME, Geurts JJ, de Vries HE, van der Valk P, van Horssen J (2010) Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10(5):411–418. https://doi.org/10.1016/j.mito.2010.05.014
Xiao MM, Zhang YQ, Wang WT, Han WJ, Lin Z, Xie RG, Cao Z, Lu N, Hu SJ, Wu SX, Dong H, Luo C (2016) Gastrodin protects against chronic inflammatory pain by inhibiting spinal synaptic potentiation. Sci Rep 6(1):37251. https://doi.org/10.1038/srep37251
Yang XD, Zhu J, Yang R, Liu JP, Li L, Zhang HB (2007) Phenolic constituents from the rhizomes of Gastrodia elata. Nat Prod Res 21(2):180–186. https://doi.org/10.1080/14786410601081997
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This work was supported by CNPq. FBB receives financial support from the FOPESQ/UFF.
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de Oliveira, M.R., Brasil, F.B. & Fürstenau, C.R. Evaluation of the Mitochondria-Related Redox and Bioenergetics Effects of Gastrodin in SH-SY5Y Cells Exposed to Hydrogen Peroxide. J Mol Neurosci 64, 242–251 (2018). https://doi.org/10.1007/s12031-018-1027-0
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DOI: https://doi.org/10.1007/s12031-018-1027-0