Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm

The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolar range and is therefore the main controller of the ER [Ca2+] level ([Ca2+]ER), which has a key role in the modulation of cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer...

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Autores: García-Casas, Paloma, Arias-del-Val, Jessica, Alvarez-Illera, Pilar, Fonteriz, Rosalba I., Montero, Mayte, Álvarez, Javier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/196696
Acceso en línea:http://hdl.handle.net/10261/196696
Access Level:acceso abierto
Palabra clave:C. elegans
Lifespan
Ca2C signaling
SERCA
Thapsigargin
Aging
Calcium
Endoplasmic reticulum
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spelling Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans wormGarcía-Casas, PalomaArias-del-Val, JessicaAlvarez-Illera, PilarFonteriz, Rosalba I.Montero, MayteÁlvarez, JavierC. elegansLifespanCa2C signalingSERCAThapsigarginAgingCalciumEndoplasmic reticulumThe sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolar range and is therefore the main controller of the ER [Ca2+] level ([Ca2+]ER), which has a key role in the modulation of cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer. Given that both cytosolic and mitochondrial Ca2+ dynamics strongly interplay with energy metabolism and nutrient-sensitive pathways, both of them involved in the aging process, we have studied the effect of SERCA inhibitors on lifespan in C. elegans. We have used thapsigargin and 2,5-Di-tert-butylhydroquinone (2,5-BHQ) as SERCA inhibitors, and the inactive analog 2,6-Di-tert-butylhydroquinone (2,6-BHQ) as a control for 2,5-BHQ. Every drug was administered to the worms either directly in the agar or via an inclusion compound with γ-cyclodextrin. The results show that 2,6-BHQ produced a small but significant increase in survival, perhaps because of its antioxidant properties. However, 2,5-BHQ produced in all the conditions a much higher increase in lifespan, and the potent and specific SERCA inhibitor thapsigargin also extended the lifespan. The effects of 2,5-BHQ and thapsigargin had a bell-shaped concentration dependence, with a maximum effect at a certain dose and smaller or even toxic effects at higher concentrations. Our data show therefore that submaximal inhibition of SERCA pumps has a pro-longevity effect, suggesting that Ca2+ signaling plays an important role in the aging process and that it could be a promising novel target pathway to act on aging.This work was supported by a grant from the Spanish Ministerio de Economía y Competitividad [BFU2014-55731-R], project cofinanced by the European Union through the European Regional Development Fund. Some C. elegans strains were provided by the Caenorhabditis Genetics Center (CGC), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). JA-d-V has a fellowship from Junta de Castilla y León (JCyL),co-financed by the Fondo Social Europeo (FSE). PG-C has a FPI fellowship from Ministerio de Economía y Competitividad.Peer reviewedFrontiers MediaMinisterio de Economía y Competitividad (España)European CommissionJunta de Castilla y LeónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/196696reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-55731-Rhttps://doi.org/10.3389/fphar.2018.00669Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1966962026-05-22T06:33:51Z
dc.title.none.fl_str_mv Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
title Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
spellingShingle Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
García-Casas, Paloma
C. elegans
Lifespan
Ca2C signaling
SERCA
Thapsigargin
Aging
Calcium
Endoplasmic reticulum
title_short Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
title_full Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
title_fullStr Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
title_full_unstemmed Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
title_sort Inhibition of sarco-endoplasmic reticulum Ca2+ ATPase extends the lifespan in C. elegans worm
dc.creator.none.fl_str_mv García-Casas, Paloma
Arias-del-Val, Jessica
Alvarez-Illera, Pilar
Fonteriz, Rosalba I.
Montero, Mayte
Álvarez, Javier
author García-Casas, Paloma
author_facet García-Casas, Paloma
Arias-del-Val, Jessica
Alvarez-Illera, Pilar
Fonteriz, Rosalba I.
Montero, Mayte
Álvarez, Javier
author_role author
author2 Arias-del-Val, Jessica
Alvarez-Illera, Pilar
Fonteriz, Rosalba I.
Montero, Mayte
Álvarez, Javier
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Junta de Castilla y León
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv C. elegans
Lifespan
Ca2C signaling
SERCA
Thapsigargin
Aging
Calcium
Endoplasmic reticulum
topic C. elegans
Lifespan
Ca2C signaling
SERCA
Thapsigargin
Aging
Calcium
Endoplasmic reticulum
description The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolar range and is therefore the main controller of the ER [Ca2+] level ([Ca2+]ER), which has a key role in the modulation of cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer. Given that both cytosolic and mitochondrial Ca2+ dynamics strongly interplay with energy metabolism and nutrient-sensitive pathways, both of them involved in the aging process, we have studied the effect of SERCA inhibitors on lifespan in C. elegans. We have used thapsigargin and 2,5-Di-tert-butylhydroquinone (2,5-BHQ) as SERCA inhibitors, and the inactive analog 2,6-Di-tert-butylhydroquinone (2,6-BHQ) as a control for 2,5-BHQ. Every drug was administered to the worms either directly in the agar or via an inclusion compound with γ-cyclodextrin. The results show that 2,6-BHQ produced a small but significant increase in survival, perhaps because of its antioxidant properties. However, 2,5-BHQ produced in all the conditions a much higher increase in lifespan, and the potent and specific SERCA inhibitor thapsigargin also extended the lifespan. The effects of 2,5-BHQ and thapsigargin had a bell-shaped concentration dependence, with a maximum effect at a certain dose and smaller or even toxic effects at higher concentrations. Our data show therefore that submaximal inhibition of SERCA pumps has a pro-longevity effect, suggesting that Ca2+ signaling plays an important role in the aging process and that it could be a promising novel target pathway to act on aging.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/196696
url http://hdl.handle.net/10261/196696
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-55731-R
https://doi.org/10.3389/fphar.2018.00669
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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