Skip to main content
SpringerLink
Log in

Vdac1 Downregulation Causes Mitochondrial Disintegration Leading to Hippocampal Neurodegeneration in Scopolamine-Induced Amnesic Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Our previous report on hippocampal proteome analysis suggested the involvement of voltage-dependent anion channel (Vdac) 1 in scopolamine-induced amnesia. Further silencing of Vdac1 in young mice reduced the recognition memory. Vdac1 is a porin protein present abundantly on outer mitochondrial membrane. It acts as a transporter of energy metabolites ATP/ADP and Ca2+ ions and helps in communication between mitochondrial matrix and cytosol. As Vdac1-associated energy metabolism may be affected during amnesia, we determined the downstream function of Vdac1 in the present study. The expression of Vdac1 and total ATP level was decreased in the hippocampus of scopolamine-induced amnesic mice. Also, the mitochondrial membrane potential, cristae organization, and morphology were disrupted leading to increased ROS generation and reduced SOD and catalase activity. On the other hand, there was increase in the expression of pro-apoptotic marker proteins (Bax, Bad, Casp 3), leading to rising degenerated neuronal cells in the dentate gyrus and Cornu ammonis 3 and 1 subregions of the hippocampus during amnesia. Further, to check whether Vdac1 downregulation is associated with neurodegeneration, we infused Vdac1 siRNA stereotaxically in the hippocampus of normal young mice. As compared to control, Vdac1 silencing decreased ATP level and mitochondrial membrane potential leading to increase in the number of degenerated neuronal cells in subregions of the hippocampus. Taken together, our study shows that downregulation of Vdac1 causes neurodegeneration through mitochondrial disintegration in the hippocampus of scopolamine-induced amnesic mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Blokland A (2005) Scopolamine-induced deficits in cognitive performance: a review of animal studies. Scopolamine Rev 1:1–76

  2. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6(11):e27265

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Gautam A, Wadhwa R, Thakur MK (2013) Involvement of hippocampal arc in amnesia and its recovery by alcoholic extract of ashwagandha leaves. Neurobiol Learn Mem 106:177–184

    Article  PubMed  Google Scholar 

  4. Baghel MS, Thakur MK (2017) Differential proteome profiling in the hippocampus of amnesic mice. Hippocampus 27:845–859

    Article  CAS  PubMed  Google Scholar 

  5. Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL, Brown SE, Sweatt JD, Craigen WJ (2002) The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J Biol Chem 277:18891–18897

    Article  CAS  PubMed  Google Scholar 

  6. Huang H, Shah K, Bradbury NA, Li C, White C (2014) Mcl-1 promotes lung cancer cell migration by directly interacting with Vdac to increase mitochondrial Ca2+ uptake and reactive oxygen species generation. Cell Death Dis 5:e1482

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Okada SF, O'Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC (2004) Voltage-dependent anion channel-1 (VDAC-1) contributes to ATP release and cell volume regulation in murine cells. J Gen Physiol 124:513–526

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Kapogiannis D, Mattson MP (2011) Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol 10:187–198

    Article  CAS  PubMed  Google Scholar 

  9. Pathak D, Shields LY, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, Kim H, Brand MD et al (2015) The role of mitochondrially derived ATP in synaptic vesicle recycling. J Biol Chem 290:22325–22236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Marsicano G, Lafenêtre P (2009) Roles of the endocannabinoid system in learning and memory. Curr Top Behav Neurosci 1:201–230

    Article  CAS  PubMed  Google Scholar 

  11. Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N (2016) Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry 79:557–567

    Article  CAS  PubMed  Google Scholar 

  12. Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, Pagano Zottola AC, Delamarre A et al (2016) A cannabinoid link between mitochondria and memory. Nature 539:555–559

    Article  CAS  PubMed  Google Scholar 

  13. Hagihara H, Toyama K, Yamasaki N, Miyakawa T (2009) Dissection of hippocampal dentate gyrus from adult mouse. J Vis Exp 17. https://doi.org/10.3791/1543

  14. Ji XF, Chi TY, Xu Q, He XL, Zhou XY, Zhang R, Zou LB (2014) Xanthoceraside ameliorates mitochondrial dysfunction contributing to the improvement of learning and memory impairment in mice with intracerebroventricular injection of aβ1–42. Evid Based Complement Alternat Med 2014:969342

    PubMed  PubMed Central  Google Scholar 

  15. Premkumar A, Simantov R (2002) Mitochondrial voltage-dependent anion channel is involved in dopamine-induced apoptosis. J Neurochem 82:345–352

    Article  CAS  PubMed  Google Scholar 

  16. Prins JM, Park S, Lurie D (2010) Decreased expression of the voltage-dependent anion channel in differentiated PC-12 and SH-SY5Y cells following low-level Pb exposure. Toxicol Sci 113:169–176

    Article  CAS  PubMed  Google Scholar 

  17. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  18. Chida J, Yamane K, Takei T, Kido H (2012) An efficient extraction method for quantitation of adenosine triphosphate in mammalian tissues and cells. Anal Chim Acta 727:8–12

    Article  CAS  PubMed  Google Scholar 

  19. Paramanik V, Thakur MK (2012) Estrogen receptor β and its domains interact with casein kinase 2, phosphokinase C, and N-myristoylation sites of mitochondrial and nuclear proteins in mouse brain. J Biol Chem 287:22305–22316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Jain K, Prasad D, Singh SB, Kohli E (2015) Hypobaric hypoxia imbalances mitochondrial dynamics in rat brain hippocampus. Neurol Res Int 2015:742059

    PubMed  PubMed Central  Google Scholar 

  21. Saetersdal T, Engedal H, Røli J, Myklebust R (1980) Calcium and magnesium levels in isolated mitochondria from human cardiac biopsies. Histochemistry 68:1–8

    Article  CAS  PubMed  Google Scholar 

  22. Mishra VK, Upadhyay AR, Pandey SK, Tripathi BD (2008) Concentrations of heavy metals and aquatic macrophytes of Govind Ballabh Pant Sagar an anthropogenic lake affected by coal mining effluent. Environ Monit Assess 141:49–58

    Article  CAS  PubMed  Google Scholar 

  23. Das L, Vinayak M (2014) Long term effect of curcumin in regulation of glycolytic pathway and angiogenesis via modulation of stress activated genes in prevention of cancer. PLoS One 9:e99583

    Article  PubMed Central  PubMed  Google Scholar 

  24. Weydert CJ, Cullen JJ (2010) Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc 5:51–66

    Article  CAS  PubMed  Google Scholar 

  25. Qiu JH, Asai A, Chi S, Saito N, Hamada H, Kirino T (2000) Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci 20:259–265

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Schmued LC, Stowers CC, Scallet AC, Xu L (2005) Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035:24–31

    Article  CAS  PubMed  Google Scholar 

  27. Ehara A, Ueda S (2009) Application of Fluoro-Jade C in acute and chronic neurodegeneration models: utilities and staining differences. Acta Histochem Cytochem 42:171–179

    Article  PubMed Central  PubMed  Google Scholar 

  28. Klein AM, Ferrante RJ (2007) The neuroprotective role of creatine. Creatine and creatine kinase in health and disease. Springer, Berlin, pp 205–243

  29. Huizing M, DePinto V, Ruitenbeek W, Trijbels FJ, van den Heuvel LP, Wendel U (1996) Importance of mitochondrial transmembrane processes in human mitochondriopathies. J Bioenerg Biomembr 28:109–114

    Article  CAS  PubMed  Google Scholar 

  30. Anflous K, Armstrong DD, Craigen WJ (2001) Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J Biol Chem 276:1954–1960

    Article  CAS  PubMed  Google Scholar 

  31. Anflous-Pharayra K, Lee N, Armstrong DL, Craigen WJ (2011) VDAC3 has differing mitochondrial functions in two types of striated muscles. Biochim Biophys Acta 1807:150–156

    Article  CAS  PubMed  Google Scholar 

  32. Loubiere C, Clavel S, Gilleron J, Harisseh R, Fauconnier J, Ben-Sahra I, Kaminski L, Laurent K et al (2017) The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells. Sci Rep 7:5040

    Article  PubMed Central  PubMed  Google Scholar 

  33. Carvalho C, Correia SC, Cardoso S, Plácido AI, Candeias E, Duarte AI, Moreira PI (2015) The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases. Expert Rev Neurother 15:867–884

    Article  CAS  PubMed  Google Scholar 

  34. Sheridan C, Martin SJ (2010) Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion 10:640–648

    Article  CAS  PubMed  Google Scholar 

  35. Chinopoulos C, Adam-Vizi V (2010) Mitochondrial Ca2+ sequestration and precipitation revisited. FEBS J 277:3637–3651

    Article  CAS  PubMed  Google Scholar 

  36. Carafoli E (2010) The fateful encounter of mitochondria with calcium: how did it happen? Biochim Biophys Acta 1797:595–606

    Article  CAS  PubMed  Google Scholar 

  37. Pivovarova NB, Nguyen HV, Winters CA, Brantner CA, Smith CL, Andrews SB (2004) Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons. J Neurosci 24:5611–5622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Wang CH, Wu SB, Wu YT, Wei YH (2013) Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp Biol Med 238:450–460

    Article  Google Scholar 

  39. Guo JY, Xia B, White E (2013) Autophagy-mediated tumor promotion. Cell 155:1216–1219

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Maharjan S, Oku M, Tsuda M, Hoseki J, Sakai Y (2014) Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition. Sci Rep 4:5896

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637

    Article  CAS  PubMed  Google Scholar 

  42. Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A 95:14681–14686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012) Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem 287:23152–23161

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V (2014) Silencing VDAC1 expression by siRNA inhibits cancer cell proliferation and tumor growth in vivo. Mol Ther Nucleic Acids 3:e159

    Article  PubMed Central  PubMed  Google Scholar 

  45. Dubey AK, Godbole A, Mathew MK (2016) Regulation of VDAC trafficking modulates cell death. Cell Death Discov 2:16085

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

Meghraj Singh Baghel thanks University Grants Commission-Centre for Advanced Study, Department of Zoology, for the award of Senior Research Fellowship. We thank Prof. TC Nag, All India Institute of Medical Sciences, New Delhi, for discussing the TEM results.

Funding

Financial support from the Department of Biotechnology, Department of Science and Technology, and Indian Council of Medical Research, Government of India, are highly acknowledged.

Author information

Authors and Affiliations

  1. Biochemistry and Molecular Biology Laboratory, Department of Zoology, Brain Research Centre, Banaras Hindu University, Varanasi, 221005, India

    Meghraj Singh Baghel & Mahendra Kumar Thakur

Authors
  1. Meghraj Singh Baghel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahendra Kumar Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahendra Kumar Thakur.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

ESM 1

(JPG 2295 kb)

ESM 2

(JPG 2103 kb)

ESM 3

(DOC 39 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baghel, M.S., Thakur, M.K. Vdac1 Downregulation Causes Mitochondrial Disintegration Leading to Hippocampal Neurodegeneration in Scopolamine-Induced Amnesic Mice. Mol Neurobiol 56, 1707–1718 (2019). https://doi.org/10.1007/s12035-018-1164-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1164-z

Keywords

Search

Navigation