Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells

Jon Andoni Sanchez, Annparo Alfonso, Marta Leiros, Eva Alonso, Mostafa E. Rateb, Marcel Jaspars, Wael E. Houssen, Rainer Peter Ebel, Luis M. Botana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
7 Downloads (Pure)


Background/Aims: The effect of four secondary metabolites isolated from sponge Spongionella, gracilins H, A, L and tetrahydroaplysulphurin-1 on Calcium ion (Ca2+) fluxes were studied in SH-SY5Y neuroblastoma cells. Methods and Results: These compounds did not modify cytosolic baseline Ca2+-levels. Nevertheless, when cytosolic Ca2+-influx through store operated calcium channels (SOC channels) was stimulated with Thapsigargin (Tg), a strong inhibition was observed in the presence of gracilin A, gracilin L and tetrahydroaplysulphurin-1. Since these compounds were able to protect mitochondria from oxidative stress, the role of this organelle in the Ca2+-influx inhibition was tested. In this sense, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and Cyclosporine A (CsA) were used. Surprisingly, both the inhibitory effect over Tg-sensitive stores and Ca2+ influx through SOC channels produced by FCCP were abolished with different potencies by Spongionella compounds in a similar way than CsA. CsA is able to avoid Mitochondrial Permeability Transition Pore (mPTP) opening. As well as CsA, Spongionella compounds reverted mPTP opening induced by FCCP. In the case of CsA the mPTP blockade is due to the direct binding to Cyclophilin D (Cyp D), a mitochondrial matrix protein. This association was also observed between gracilin L and tetrahydroaplysulphurin-1 and Cyp D. Therefore, Spongionella compounds modulate mitochondrial activity by preventing mPTP opening by binding to CypD. Conclusions: These effects make Spongionella compounds as new family of compounds with promising activity in human diseases where mitochondrial alterations are implicated. Copyright (C) 2015 S. Karger AG, Basel

Original languageEnglish
Pages (from-to)779-792
Number of pages14
JournalCellular Physiology and Biochemistry
Issue number2
Publication statusPublished - Sept 2015

Bibliographical note

The research leading to these results has received funding from the following FEDER cofounded-grants. From CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01, AGL2014-58210-R, and Consellería de Cultura, Educación e OrdenaciónUniversitaria, GRC2013-016, and through AxenciaGalega de Innovación, Spain, ITC-20133020 SINTOX. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD.

From the European Union's Seventh Framework Programme managed by REA - Research Executive Agency (FP7/2007-2013) under grant agreement 312184 PHARMASEA. Jon Andoni Sánchez is supported by a fellowship from Plan Galego de Investigación e Crecemento, Xunta de Galicia, Spain.


  • Calcium
  • SOC Channels
  • Mitochondria
  • Cyclophilin D
  • Cyclosporine A
  • Spongionella sp.
  • Permeability transition pore
  • Cyclosporine-A
  • Alzheimers-Disease
  • CA2+ uptake
  • Death
  • Inhibition
  • Channels
  • Pharmacology
  • Reticulum


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