Molecular Neurobiology

, Volume 56, Issue 10, pp 6964–6975 | Cite as

Synergy in Disruption of Mitochondrial Dynamics by Aβ (1-42) and Glia Maturation Factor (GMF) in SH-SY5Y Cells Is Mediated Through Alterations in Fission and Fusion Proteins

  • Mohammad Ejaz Ahmed
  • Govindhasamy Pushpavathi Selvakumar
  • Duraisamy Kempuraj
  • Ramasamy Thangavel
  • Shireen Mentor
  • Iuliia Dubova
  • Sudhanshu P. Raikwar
  • Smita Zaheer
  • Shankar Iyer
  • Asgar ZaheerEmail author


The pathological form of amyloid beta (Aβ) peptide is shown to be toxic to the mitochondria and implicates this organelle in the progression and pathogenesis of Alzheimer’s disease (AD). Mitochondria are dynamic structures constantly undergoing fission and fusion, and altering their shape and size while traveling through neurons. Mitochondrial fission (Drp1, Fis1) and fusion (OPA1, Mfn1, and Mfn2) proteins are balanced in healthy neuronal cells. Glia maturation factor (GMF), a neuroinflammatory protein isolated and cloned in our laboratory plays an important role in the pathogenesis of AD. We hypothesized that GMF, a brain-localized inflammatory protein, promotes oxidative stress–mediated disruption of mitochondrial dynamics by alterations in mitochondrial fission and fusion proteins which eventually leads to apoptosis in the Aβ (1-42)–treated human neuroblastoma (SH-SY5Y) cells. The SH-SY5Y cells were incubated with GMF and Aβ (1-42) peptide, and mitochondrial fission and fusion proteins were analyzed by immunofluorescence, western blotting, and co-immunoprecipitation. We report that SH-SY5Y cells incubated with GMF and Aβ (1-42) promote mitochondrial fragmentation, by potentiating oxidative stress, mitophagy and shifts in the Bax/Bcl2 expression and release of cytochrome-c, and eventual apoptosis. In the present study, we show that GMF and Aβ treatments significantly upregulate fission proteins and downregulate fusion proteins. The study shows that extracellular GMF is an important inflammatory mediator that mediates mitochondrial dynamics by altering the balance in fission and fusion proteins and amplifies similar effects promoted by Aβ. Upregulated GMF in the presence of Aβ could be an additional risk factor for AD, and their synergistic actions need to be explored as a potential therapeutic target to suppress the progression of AD.


Alzheimer’s disease Amyloid-beta Glia maturation factor Mitochondrial dynamics SH-SY5Y cells 


Funding Information

This work was supported by National Institutes of Health Grants NS073670 and AG048205, and Veterans Affairs Merit Award I01BX002477 and Veterans Affairs Research Career Scientist Award to AZ.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639. CrossRefGoogle Scholar
  2. 2.
    Thangavel R, Kempuraj D, Zaheer S, Raikwar S, Ahmed ME, Selvakumar GP, Iyer SS, Zaheer A (2017) Glia maturation factor and mitochondrial uncoupling proteins 2 and 4 expression in the temporal cortex of Alzheimer’s disease brain. Front Aging Neurosci 9:150. CrossRefGoogle Scholar
  3. 3.
    Qu M, Zhou Z, Xu S, Chen C, Yu Z, Wang D (2011) Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells. Brain Res 1368:336–345. CrossRefGoogle Scholar
  4. 4.
    Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23(2):64–71. CrossRefGoogle Scholar
  5. 5.
    Lu Y, Wang R, Dong Y, Tucker D, Zhao N, Ahmed ME, Zhu L, Liu TC et al (2017) Low-level laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging 49:165–182. CrossRefGoogle Scholar
  6. 6.
    Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of mitochondrial dysfunction in Alzheimer’s disease. Mol Neurobiol 53(9):6078–6090. CrossRefGoogle Scholar
  7. 7.
    Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337(6098):1062–1065. CrossRefGoogle Scholar
  8. 8.
    Skulachev VP (2001) Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 26(1):23–29CrossRefGoogle Scholar
  9. 9.
    Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26(2):207–210. CrossRefGoogle Scholar
  10. 10.
    Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, Rossignol R (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120 (Pt 5:838–848. CrossRefGoogle Scholar
  11. 11.
    Elgass K, Pakay J, Ryan MT, Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochim Biophys Acta 1833(1):150–161. CrossRefGoogle Scholar
  12. 12.
    Galluzzi L, Blomgren K, Kroemer G (2009) Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 10(7):481–494. CrossRefGoogle Scholar
  13. 13.
    Satou T, Cummings BJ, Cotman CW (1995) Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer’s disease brain increases with disease severity. Brain Res 697(1–2):35–43CrossRefGoogle Scholar
  14. 14.
    Moreira PI, Duarte AI, Santos MS, Rego AC, Oliveira CR (2009) An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer’s disease. J Alzheimers Dis 16(4):741–761. CrossRefGoogle Scholar
  15. 15.
    Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802(1):2–10. CrossRefGoogle Scholar
  16. 16.
    Steardo L Jr, Bronzuoli MR, Iacomino A, Esposito G, Steardo L, Scuderi C (2015) Does neuroinflammation turn on the flame in Alzheimer’s disease? Focus on astrocytes. Front Neurosci 9:259. CrossRefGoogle Scholar
  17. 17.
    Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2016) Astroglia dynamics in ageing and Alzheimer’s disease. Curr Opin Pharmacol 26:74–79. CrossRefGoogle Scholar
  18. 18.
    Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57(2):483–490CrossRefGoogle Scholar
  19. 19.
    Lim R, Zaheer A, Lane WS (1990) Complete amino acid sequence of bovine glia maturation factor beta. Proc Natl Acad Sci U S A 87(14):5233–5237CrossRefGoogle Scholar
  20. 20.
    Zaheer A, Fink BD, Lim R (1993) Expression of glia maturation factor beta mRNA and protein in rat organs and cells. J Neurochem 60(3):914–920CrossRefGoogle Scholar
  21. 21.
    Choudhury A, Marks DL, Proctor KM, Gould GW, Pagano RE (2006) Regulation of caveolar endocytosis by syntaxin 6-dependent delivery of membrane components to the cell surface. Nat Cell Biol 8(4):317–328. CrossRefGoogle Scholar
  22. 22.
    Aerbajinai W, Liu L, Zhu J, Kumkhaek C, Chin K, Rodgers GP (2016) Glia maturation factor-gamma regulates monocyte migration through modulation of beta1-integrin. J Biol Chem 291(16):8549–8564. CrossRefGoogle Scholar
  23. 23.
    Afeseh Ngwa H, Kanthasamy A, Anantharam V, Song C, Witte T, Houk R, Kanthasamy AG (2009) Vanadium induces dopaminergic neurotoxicity via protein kinase Cdelta dependent oxidative signaling mechanisms: relevance to etiopathogenesis of Parkinson’s disease. Toxicol Appl Pharmacol 240(2):273–285. CrossRefGoogle Scholar
  24. 24.
    Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E (2000) Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 6(4):1205–1218Google Scholar
  25. 25.
    Selvakumar GP, Iyer SS, Kempuraj D, Raju M, Thangavel R, Saeed D, Ahmed ME, Zahoor H et al (2018) Glia maturation factor dependent inhibition of mitochondrial PGC-1alpha triggers oxidative stress-mediated apoptosis in N27 rat dopaminergic neuronal cells. Mol Neurobiol 55:7132–7152. CrossRefGoogle Scholar
  26. 26.
    Ahmed ME, Dong Y, Lu Y, Tucker D, Wang R, Zhang Q (2017) Beneficial effects of a CaMKIIalpha inhibitor TatCN21 peptide in global cerebral ischemia. J Mol Neurosci 61(1):42–51. CrossRefGoogle Scholar
  27. 27.
    Kempuraj D, Selvakumar GP, Thangavel R, Ahmed ME, Zaheer S, Kumar KK, Yelam A, Kaur H et al (2018) Glia maturation factor and mast cell-dependent expression of inflammatory mediators and proteinase activated receptor-2 in neuroinflammation. J Alzheimers Dis 66(3):1117–1129. CrossRefGoogle Scholar
  28. 28.
    Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288(38):27584–27593. CrossRefGoogle Scholar
  29. 29.
    Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105(41):15803–15808. CrossRefGoogle Scholar
  30. 30.
    Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8(10):939–944. CrossRefGoogle Scholar
  31. 31.
    Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9(7):505–518. CrossRefGoogle Scholar
  32. 32.
    Baloyannis SJ (2006) Mitochondrial alterations in Alzheimer’s disease. J Alzheimers Dis 9(2):119–126CrossRefGoogle Scholar
  33. 33.
    Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462(2):245–253. CrossRefGoogle Scholar
  34. 34.
    Moreira PI (2012) Alzheimer’s disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin. J Alzheimers Dis 30(Suppl 2):S199–S215. CrossRefGoogle Scholar
  35. 35.
    Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnaune-Pelloquin L, Davezac N et al (2016) Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis 90:3–19. CrossRefGoogle Scholar
  36. 36.
    Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252. CrossRefGoogle Scholar
  37. 37.
    Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751–780. CrossRefGoogle Scholar
  38. 38.
    Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR (1994) Alterations of cerebral metabolism in probable Alzheimer’s disease: a preliminary study. Neurobiol Aging 15(1):117–132CrossRefGoogle Scholar
  39. 39.
    Terni B, Boada J, Portero-Otin M, Pamplona R, Ferrer I (2010) Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of Alzheimer’s disease pathology. Brain Pathol 20(1):222–233. CrossRefGoogle Scholar
  40. 40.
    Sullivan PG, Brown MR (2005) Mitochondrial aging and dysfunction in Alzheimer’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 29(3):407–410. CrossRefGoogle Scholar
  41. 41.
    Freund-Levi Y, Vedin I, Hjorth E, Basun H, Faxen Irving G, Schultzberg M, Eriksdotter M, Palmblad J et al (2014) Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer’s disease: the OmegAD study. J Alzheimers Dis 42(3):823–831. CrossRefGoogle Scholar
  42. 42.
    Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842(8):1240–1247. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mohammad Ejaz Ahmed
    • 1
    • 2
  • Govindhasamy Pushpavathi Selvakumar
    • 1
    • 2
  • Duraisamy Kempuraj
    • 1
    • 2
  • Ramasamy Thangavel
    • 1
    • 2
  • Shireen Mentor
    • 1
    • 3
  • Iuliia Dubova
    • 1
    • 2
  • Sudhanshu P. Raikwar
    • 1
    • 2
  • Smita Zaheer
    • 1
  • Shankar Iyer
    • 1
    • 2
  • Asgar Zaheer
    • 1
    • 2
    Email author
  1. 1.Department of Neurology, and Center for Translational Neuroscience, School of MedicineUniversity of MissouriColumbiaUSA
  2. 2.Harry S. Truman Memorial Veterans HospitalColumbiaUSA
  3. 3.Department of Medical BiosciencesUniversity of the Western CapeCape TownRepublic of South Africa

Personalised recommendations