Evaluation of fisetin as a potential inducer of mitochondrial biogenesis in SH-SY5Y neuronal cells

Document Type : Original Article

Author

Department of Genetics and Bioengineering, Alanya Alaaddin Keykubat University, Alanya, Antalya, Turkey

Abstract

Objective(s): Increasing evidence implicates impaired mitochondrial biogenesis as an important contributor to mitochondrial dysfunction, which plays a central role in the pathogenesis of neurodegenerative diseases including Parkinson’s disease (PD). For this reason, targeting mitochondrial biogenesis may present a promising therapeutic strategy for PD. The present study attempted to investigate the effects of fisetin, a dietary flavonoid, on mitochondrial biogenesis and the expression of PD-associated genes in neuronal cells.
Materials and Methods: The effects of fisetin on mitochondrial biogenesis were evaluated by three different approaches; PGC-1α and TFAM mRNA expressions by RT-qPCR, mitochondrial DNA (mtDNA) content by quantitative PCR and mitochondrial mass by MitoTracker staining. Next, a PCR array was performed to evaluate the effects of fisetin on the expression profile of PD-associated genes. Finally, the common targets of fisetin and PD were analyzed by in silico analyses
Results: The results demonstrated that fisetin treatment can increase PGC-1α and TFAM mRNA levels, mtDNA copy number, and mitochondrial mass in neuronal cells. Fisetin also altered the expressions of some PD-related genes involved in neuroprotection and neuronal differentiation. Moreover, the bioinformatics analyses suggested that the AKT1-GSK3B signaling might be responsible for the potential neuroprotective effects of fisetin.
Conclusion: Collectively, these results imply that fisetin could modulate some neuroprotective mechanisms including mitochondrial biogenesis, and may serve as a potential drug candidate for PD.

Keywords

Main Subjects

References

1. Tan EK, Chao YX, West A, Chan LL, Poewe W, Jankovic J. Parkinson disease and the immune system - associations, mechanisms and therapeutics. Nat Rev Neurol 2020; 16:303–318.
2. Dauer W, Przedborski S. Parkinson’s disease: Mechanisms and models. Neuron 2003; 39:889–909. 
3. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022; 22:657-673.
4. Picca A, Calvani R, Coelho-Junior HJ, Landi F, Bernabei R, Marzetti E. Mitochondrial dysfunction, oxidative stress, and neuroinflammation: Intertwined roads to neurodegeneration. Anti-oxidants (Basel) 2020; 9:1-21.
5. Vijiaratnam N, Simuni T, Bandmann O, Morris HR, Foltynie T. Progress towards therapies for disease modification in Parkinson’s disease. Lancet Neurol 2021; 20:559-572.
6. Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: How and where. Int J Mol Sci 2021; 22:1-11.
7. Rugarli EI, Langer T. Mitochondrial quality control: A matter of life and death for neurons. EMBO J 2012; 31:1336–1349.
8. Drake JC, Wilson RJ, Yan Z. Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J 2016; 30:13-22.
9. Simmons EC, Scholpa NE, Schnellmann RG. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol 2020; 329:1-38.
10. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick S, Watt ML, et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2010; 2:52ra73.
11. Zhu JH, Gusdon AM, Cimen H, Van Houten B, Koc E, Chu CT. Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: Dual roles for ERK1/2. Cell Death Dis 2012; 3:e312.
12. Lall RK, Adhami VM, Mukhtar H. Dietary flavonoid fisetin for cancer prevention and treatment. Mol Nutr Food Res 2016; 60:1396–1405.
13. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: A dietary anti-oxidant for health promotion. Antioxid Redox Signal 2013; 19:151–162.
14. Sagara Y, Vanhnasy J, Maher P. Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation. J Neurochem 2004; 90:1144–1155.
15. Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ. Distinctive anti-oxidant and antiinflammatory effects of flavonols. J Agric Food Chem 2006; 54:9798–9804.
16. Patel MY, Panchal HV, Ghribi O, Benzeroual KE. The neuroprotective effect of fisetin in the MPTP model of Parkinson’s disease. J Parkinsons Dis 2012; 2:287–302.
17. Rajendran M, Ramachandran R. Fisetin protects against rotenone-induced neurotoxicity through signaling pathway. Front Biosci (Elite Ed) 2019; 11:20–28.
18. Watanabe R, Kurose T, Morishige Y, Fujimori K. Protective effects of fisetin against 6-OHDA-induced apoptosis by activation of PI3K-Akt signaling in human neuroblastoma SH-SY5Y cells. Neurochem Res 2018; 43:488–499.
19. Rosado-Ramos R, Godinho-Pereira J, Marques D, Figueira I, Fleming Outeiro T, Menezes R, et al. Small molecule fisetin modulates alpha-synuclein aggregation. Molecules 2021; 26:1-17.
20. Chen TJ, Feng Y, Liu T, Wu TT, Chen YJ, Li X, et al. Fisetin regulates gut microbiota and exerts neuroprotective effect on mouse model of Parkinson’s disease. Fronti Neurosci 2020; 14:1-14.
21. Alikatte K, Palle S, Rajendra Kumar J, Pathakala N. Fisetin improved rotenone-induced behavioral deficits, oxidative changes, and mitochondrial dysfunctions in rat model of Parkinson’s disease. J Diet Suppl 2021; 18:57–71.
22. Ay M. Vanillic acid induces mitochondrial biogenesis in SH-SY5Y cells. Mol Biol Rep 2022; 49:4443–4449.
23. Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47:W357–W364.
24. Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M, et al. GeneCards Version 3: The human gene integrator. Database (Oxford) 2010; baq020.
25. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47:D607–D613.
26. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: The central role of PGC-1alpha. Cardiovasc Res 2008; 79:208–217.
27. Pang SY, Ho PW, Liu HF, Leung CT, Li L, Chang EES, et al. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease. Transl Neurodegener 2019; 8:1-11.
28. Kalia LV, Lang AE. Parkinson’s disease. Lancet (London, England) 2015; 386:896–912.
29. González-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 2021; 599:650–656.
30. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54:823–827.
31. Ay M, Luo J, Langley M, Jin H, Anantharam V, Kanthasamy A, et al. Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson’s Disease. J Neurochem 2017; 141:766–782.
32. Khatri DK, Juvekar AR. Neuroprotective effect of curcumin as evinced by abrogation of rotenone-induced motor deficits, oxidative and mitochondrial dysfunctions in mouse model of Parkinson’s disease. Pharmacol Biochem Behav 2016; 150-151:39–47.
33. Peng K, Tao Y, Zhang J, Wang J, Ye F, Dan G, et al. Resveratrol regulates mitochondrial biogenesis and fission/fusion to attenuate rotenone-induced neurotoxicity. Oxid Med Cell Longev 2016; 1-12.
34. Cho I, Song HO, Cho JH. Flavonoids mitigate neurodegeneration in aged Caenorhabditis elegans by mitochondrial uncoupling. Food Sci Nutr 2020; 8:6633–6642. 
35. Asghar M, Odeh A, Fattahi AJ, Henriksson AE, Miglar A, Khosousi S, et al. Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson’s disease and Lewy body dementia. Sci Rep 2022; 12:1-23.
36. Gui YX, Xu ZP, Lv W, Zhao JJ, Hu XY. Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson’s disease. Parkinsonism Relat Disord 2015; 21:282–286.
37. Cui J, Fan J, Li H, Zhang J, Tong J. Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway. Neuroreport 2021; 32:296–305.
38. Poulin JF, Zou J, Drouin-Ouellet J, Kim KY, Cicchetti F, Awatramani RB. Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling. Cell Rep 2014; 9:930–943.
39. Bauer M, Szulc J, Meyer M, Jensen CH, Terki TA, Meixner A, et al. Delta-like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons. J Neurochem 2008; 104:1101–1115.
40. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H, et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 2006; 15:883–895.
41. Harmon JL, Wills LP, McOmish CE, Demireva EY, Gingrich JA, Beeson CC, et al. 5-HT2 receptor regulation of mitochondrial genes: unexpected pharmacological effects of agonists and antagonists. J Pharmacol Exp Ther 2016; 357:1–9.
42. Zonta B, Desmazieres A, Rinaldi A, Tait S, Sherman DL, Nolan MF, et al. A critical role for Neurofascin in regulating action potential initiation through maintenance of the axon initial segment. Neuron 2011; 69:945–956.
43. Yang W, Wang G, Wang CE, Guo X, Yin P, Gao J, et al. Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain. J Neurosci 2015; 35:8345–8358.
44. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378:785–789.
45. Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network. Cell 2017; 169:381–405.
46. Romorini L, Garate X, Neiman G, Luzzani C, Furmento VA, Guberman AS, et al. AKT/GSK3β signaling pathway is critically involved in human pluripotent stem cell survival. Sci Rep 2016; 6: 1-15.
47. Molagoda IMN, Karunarathne WAHM, Park SR, Choi YH, Park EK, Jin CY, et al. GSK-3β-targeting fisetin promotes melanogenesis in B16F10 melanoma cells and zebrafish larvae through β-catenin activation. Int J Mol Sci 2020; 21:1-20.
48. Li J, Ma S, Chen J, Hu K, Li Y, Zhang Z, et al. GSK-3β contributes to parkinsonian dopaminergic neuron death: Evidence from conditional knockout mice and tideglusib. Front Mol Neurosci 2020; 13:1-12.
49. Martin SA, Souder DC, Miller KN, Clark JP, Sagar AK, Eliceiri KW, et al. GSK3β regulates brain energy metabolism. Cell Rep 2018; 23:1922–1931.e4.
50. Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO. Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol 2017; 54:2269–2285.
51. Piantadosi CA, Suliman HB. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem 2006; 281:324–333.
52. Shaerzadeh F, Motamedi F, Khodagholi F. Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer’s disease. Cell Mol Neurobiol 2014; 34:1223–1233.
53. Zhu JL, Wu YY, Wu D, Luo WF, Zhang ZQ, Liu CF. SC79, a novel Akt activator, protects dopaminergic neuronal cells from MPP+ and rotenone. Mol Cell Biochem 2019; 461:81–89.
 
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 11
November 2023
Pages 1320-1325

Files

Share

How to cite

Statistics