Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress

Autores
Saporito Magriñá, Christian Martín; Musacco Sebio, Rosario Natalia; Andrieux, Geoffroy; Kook, Lucas; Orrego, Manuel Tomás; Tuttolomondo, María Victoria; Desimone, Martín Federico; Boerries, Melanie; Borner, Christoph; Repetto, Marisa Gabriela
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.
Fil: Saporito Magriñá, Christian Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Musacco Sebio, Rosario Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Andrieux, Geoffroy. German Cancer Research Center; Alemania. Universität Freiburg Im Breisgau; Alemania
Fil: Kook, Lucas. Universität Freiburg Im Breisgau; Alemania
Fil: Orrego, Manuel Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Tuttolomondo, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; Argentina
Fil: Desimone, Martín Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina
Fil: Boerries, Melanie. Universität Freiburg Im Breisgau; Alemania
Fil: Borner, Christoph. Universität Freiburg Im Breisgau; Alemania
Fil: Repetto, Marisa Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Universidad de Buenos Aires; Argentina
Materia
COPPER
OXIDATIVE STRESS
ANTIOXIDANT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/87018
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stressSaporito Magriñá, Christian MartínMusacco Sebio, Rosario NataliaAndrieux, GeoffroyKook, LucasOrrego, Manuel TomásTuttolomondo, María VictoriaDesimone, Martín FedericoBoerries, MelanieBorner, ChristophRepetto, Marisa GabrielaCOPPEROXIDATIVE STRESSANTIOXIDANThttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.Fil: Saporito Magriñá, Christian Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Musacco Sebio, Rosario Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Andrieux, Geoffroy. German Cancer Research Center; Alemania. Universität Freiburg Im Breisgau; AlemaniaFil: Kook, Lucas. Universität Freiburg Im Breisgau; AlemaniaFil: Orrego, Manuel Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Tuttolomondo, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; ArgentinaFil: Desimone, Martín Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Boerries, Melanie. Universität Freiburg Im Breisgau; AlemaniaFil: Borner, Christoph. Universität Freiburg Im Breisgau; AlemaniaFil: Repetto, Marisa Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Universidad de Buenos Aires; ArgentinaRoyal Society of Chemistry2018-12-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/87018Saporito Magriñá, Christian Martín; Musacco Sebio, Rosario Natalia; Andrieux, Geoffroy; Kook, Lucas; Orrego, Manuel Tomás; et al.; Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress; Royal Society of Chemistry; Metallomics; 10; 12; 3-12-2018; 1743-17541756-5901CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1039/c8mt00182kinfo:eu-repo/semantics/altIdentifier/url/https://pubs.rsc.org/en/content/articlelanding/2018/MT/C8MT00182K#!divAbstractinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:06:28Zoai:ri.conicet.gov.ar:11336/87018instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:06:28.495CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
title Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
spellingShingle Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
Saporito Magriñá, Christian Martín
COPPER
OXIDATIVE STRESS
ANTIOXIDANT
title_short Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
title_full Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
title_fullStr Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
title_full_unstemmed Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
title_sort Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress
dc.creator.none.fl_str_mv Saporito Magriñá, Christian Martín
Musacco Sebio, Rosario Natalia
Andrieux, Geoffroy
Kook, Lucas
Orrego, Manuel Tomás
Tuttolomondo, María Victoria
Desimone, Martín Federico
Boerries, Melanie
Borner, Christoph
Repetto, Marisa Gabriela
author Saporito Magriñá, Christian Martín
author_facet Saporito Magriñá, Christian Martín
Musacco Sebio, Rosario Natalia
Andrieux, Geoffroy
Kook, Lucas
Orrego, Manuel Tomás
Tuttolomondo, María Victoria
Desimone, Martín Federico
Boerries, Melanie
Borner, Christoph
Repetto, Marisa Gabriela
author_role author
author2 Musacco Sebio, Rosario Natalia
Andrieux, Geoffroy
Kook, Lucas
Orrego, Manuel Tomás
Tuttolomondo, María Victoria
Desimone, Martín Federico
Boerries, Melanie
Borner, Christoph
Repetto, Marisa Gabriela
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COPPER
OXIDATIVE STRESS
ANTIOXIDANT
topic COPPER
OXIDATIVE STRESS
ANTIOXIDANT
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.
Fil: Saporito Magriñá, Christian Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Musacco Sebio, Rosario Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Andrieux, Geoffroy. German Cancer Research Center; Alemania. Universität Freiburg Im Breisgau; Alemania
Fil: Kook, Lucas. Universität Freiburg Im Breisgau; Alemania
Fil: Orrego, Manuel Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Tuttolomondo, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; Argentina
Fil: Desimone, Martín Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química Analítica Instrumental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina
Fil: Boerries, Melanie. Universität Freiburg Im Breisgau; Alemania
Fil: Borner, Christoph. Universität Freiburg Im Breisgau; Alemania
Fil: Repetto, Marisa Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Universidad de Buenos Aires; Argentina
description Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.
publishDate 2018
dc.date.none.fl_str_mv 2018-12-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/87018
Saporito Magriñá, Christian Martín; Musacco Sebio, Rosario Natalia; Andrieux, Geoffroy; Kook, Lucas; Orrego, Manuel Tomás; et al.; Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress; Royal Society of Chemistry; Metallomics; 10; 12; 3-12-2018; 1743-1754
1756-5901
CONICET Digital
CONICET
url http://hdl.handle.net/11336/87018
identifier_str_mv Saporito Magriñá, Christian Martín; Musacco Sebio, Rosario Natalia; Andrieux, Geoffroy; Kook, Lucas; Orrego, Manuel Tomás; et al.; Copper-induced cell death and the protective role of glutathione: The implication of impaired protein folding rather than oxidative stress; Royal Society of Chemistry; Metallomics; 10; 12; 3-12-2018; 1743-1754
1756-5901
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1039/c8mt00182k
info:eu-repo/semantics/altIdentifier/url/https://pubs.rsc.org/en/content/articlelanding/2018/MT/C8MT00182K#!divAbstract
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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