Kinetic and protective role of autophagy in manganese-exposed BV-2 cells

Autores
Porte Alcon, Soledad; Gorojod, Roxana Mayra; Kotler, Monica Lidia
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in the brain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options for this disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand the cellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidence indicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remain unknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglial cells. These species generated by Mn2+ induce lysosomal alterations, LMP, cathepsins release and cell death. Besides, we described for the first time the kinetic of Mn2+-induced autophagy in BV-2 microglial cells and its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expression levels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated with lysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy and retarded Mn2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subset of lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We propose that 2 h Mn2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, the accumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may represent a valuable contribution to future research concerning manganism therapies.
Fil: Porte Alcon, Soledad. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Gorojod, Roxana Mayra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kotler, Monica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Materia
AUTOPHAGY
LYSOSOMES
MANGANESE
MICROGLIA
REACTIVE OXYGEN SPECIES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/182473
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/182473
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Kinetic and protective role of autophagy in manganese-exposed BV-2 cellsPorte Alcon, SoledadGorojod, Roxana MayraKotler, Monica LidiaAUTOPHAGYLYSOSOMESMANGANESEMICROGLIAREACTIVE OXYGEN SPECIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in the brain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options for this disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand the cellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidence indicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remain unknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglial cells. These species generated by Mn2+ induce lysosomal alterations, LMP, cathepsins release and cell death. Besides, we described for the first time the kinetic of Mn2+-induced autophagy in BV-2 microglial cells and its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expression levels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated with lysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy and retarded Mn2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subset of lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We propose that 2 h Mn2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, the accumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may represent a valuable contribution to future research concerning manganism therapies.Fil: Porte Alcon, Soledad. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Gorojod, Roxana Mayra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Kotler, Monica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaElsevier Science2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/182473Porte Alcon, Soledad; Gorojod, Roxana Mayra; Kotler, Monica Lidia; Kinetic and protective role of autophagy in manganese-exposed BV-2 cells; Elsevier Science; Biochimica et Biophysica Acta-Molecular Cell Research; 1867; 10; 10-2020; 1-150167-48891879-2596CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0167488920301452info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbamcr.2020.118787info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:45:56Zoai:ri.conicet.gov.ar:11336/182473instacron: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:34982025-09-03 09:45:56.586CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
title Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
spellingShingle Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
Porte Alcon, Soledad
AUTOPHAGY
LYSOSOMES
MANGANESE
MICROGLIA
REACTIVE OXYGEN SPECIES
title_short Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
title_full Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
title_fullStr Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
title_full_unstemmed Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
title_sort Kinetic and protective role of autophagy in manganese-exposed BV-2 cells
dc.creator.none.fl_str_mv Porte Alcon, Soledad
Gorojod, Roxana Mayra
Kotler, Monica Lidia
author Porte Alcon, Soledad
author_facet Porte Alcon, Soledad
Gorojod, Roxana Mayra
Kotler, Monica Lidia
author_role author
author2 Gorojod, Roxana Mayra
Kotler, Monica Lidia
author2_role author
author
dc.subject.none.fl_str_mv AUTOPHAGY
LYSOSOMES
MANGANESE
MICROGLIA
REACTIVE OXYGEN SPECIES
topic AUTOPHAGY
LYSOSOMES
MANGANESE
MICROGLIA
REACTIVE OXYGEN SPECIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in the brain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options for this disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand the cellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidence indicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remain unknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglial cells. These species generated by Mn2+ induce lysosomal alterations, LMP, cathepsins release and cell death. Besides, we described for the first time the kinetic of Mn2+-induced autophagy in BV-2 microglial cells and its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expression levels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated with lysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy and retarded Mn2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subset of lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We propose that 2 h Mn2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, the accumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may represent a valuable contribution to future research concerning manganism therapies.
Fil: Porte Alcon, Soledad. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Gorojod, Roxana Mayra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kotler, Monica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
description Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in the brain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options for this disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand the cellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidence indicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remain unknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglial cells. These species generated by Mn2+ induce lysosomal alterations, LMP, cathepsins release and cell death. Besides, we described for the first time the kinetic of Mn2+-induced autophagy in BV-2 microglial cells and its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expression levels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated with lysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy and retarded Mn2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subset of lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We propose that 2 h Mn2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, the accumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may represent a valuable contribution to future research concerning manganism therapies.
publishDate 2020
dc.date.none.fl_str_mv 2020-10
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/11336/182473
Porte Alcon, Soledad; Gorojod, Roxana Mayra; Kotler, Monica Lidia; Kinetic and protective role of autophagy in manganese-exposed BV-2 cells; Elsevier Science; Biochimica et Biophysica Acta-Molecular Cell Research; 1867; 10; 10-2020; 1-15
0167-4889
1879-2596
CONICET Digital
CONICET
url http://hdl.handle.net/11336/182473
identifier_str_mv Porte Alcon, Soledad; Gorojod, Roxana Mayra; Kotler, Monica Lidia; Kinetic and protective role of autophagy in manganese-exposed BV-2 cells; Elsevier Science; Biochimica et Biophysica Acta-Molecular Cell Research; 1867; 10; 10-2020; 1-15
0167-4889
1879-2596
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0167488920301452
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbamcr.2020.118787
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
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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