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 journalArticle

7 Citations (Scopus)
3 Downloads (Pure)

Abstract

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
Volume37
Issue number2
DOIs
Publication statusPublished - Sep 2015

Keywords

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

Cite this

Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells. / Andoni Sanchez, Jon; Alfonso, Annparo; Leiros, Marta; Alonso, Eva; Rateb, Mostafa E.; Jaspars, Marcel; Houssen, Wael E.; Ebel, Rainer Peter; Botana, Luis M.

In: Cellular Physiology and Biochemistry, Vol. 37, No. 2, 09.2015, p. 779-792.

Research output: Contribution to journalArticle

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abstract = "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",
keywords = "Calcium, SOC Channels, Mitochondria, Cyclophilin D, Cyclosporine A, Spongionella sp., Permeability transition pore, Cyclosporine-A, Alzheimers-Disease, CA2+ uptake, Death, Inhibition, Channels, Pharmacology, Reticulum",
author = "{Andoni Sanchez}, Jon and Annparo Alfonso and Marta Leiros and Eva Alonso and Rateb, {Mostafa E.} and Marcel Jaspars and Houssen, {Wael E.} and Ebel, {Rainer Peter} and Botana, {Luis M.}",
note = "cknowledgements The research leading to these results has received funding from the following FEDER cofounded-grants. From CDTI and Technological Funds, supported by Ministerio de Econom{\'i}a y Competitividad, AGL2012-40185-CO2-01, AGL2014-58210-R, and Conseller{\'i}a de Cultura, Educaci{\'o}n e Ordenaci{\'o}nUniversitaria, GRC2013-016, and through AxenciaGalega de Innovaci{\'o}n, 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 S{\'a}nchez is supported by a fellowship from Plan Galego de Investigaci{\'o}n e Crecemento, Xunta de Galicia, Spain.",
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TY - JOUR

T1 - Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells

AU - Andoni Sanchez, Jon

AU - Alfonso, Annparo

AU - Leiros, Marta

AU - Alonso, Eva

AU - Rateb, Mostafa E.

AU - Jaspars, Marcel

AU - Houssen, Wael E.

AU - Ebel, Rainer Peter

AU - Botana, Luis M.

N1 - cknowledgements 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.

PY - 2015/9

Y1 - 2015/9

N2 - 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

AB - 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

KW - Calcium

KW - SOC Channels

KW - Mitochondria

KW - Cyclophilin D

KW - Cyclosporine A

KW - Spongionella sp.

KW - Permeability transition pore

KW - Cyclosporine-A

KW - Alzheimers-Disease

KW - CA2+ uptake

KW - Death

KW - Inhibition

KW - Channels

KW - Pharmacology

KW - Reticulum

U2 - 10.1159/000430395

DO - 10.1159/000430395

M3 - Article

VL - 37

SP - 779

EP - 792

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

SN - 1015-8987

IS - 2

ER -