Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease

Oxidative phosphorylation system (OXPHOS) deficiencies are rare diseases but constitute the most frequent inborn errors of metabolism. We analyzed the autophagy route in 11 skin fibroblast cultures derived from patients with well characterized and distinct OXPHOS defects. Mitochondrial membrane pote...

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Detalles Bibliográficos
Autores: Morán, María, Delmiro, Aitor, Blázquez, Alberto, Ugalde, Cristina, Arenas, Joaquín, Martín, Miguel A.
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/670426
Acceso en línea:http://hdl.handle.net/10486/670426
https://dx.doi.org/10.1016/j.bbadis.2014.03.013
Access Level:acceso abierto
Palabra clave:Autophagosome
Autophagy
Lysosome
Mitophagy
OXPHOS deficiency
Parkin
Biología y Biomedicina / Biología
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spelling Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial diseaseMorán, MaríaDelmiro, AitorBlázquez, AlbertoUgalde, CristinaArenas, JoaquínMartín, Miguel A.AutophagosomeAutophagyLysosomeMitophagyOXPHOS deficiencyParkinBiología y Biomedicina / BiologíaOxidative phosphorylation system (OXPHOS) deficiencies are rare diseases but constitute the most frequent inborn errors of metabolism. We analyzed the autophagy route in 11 skin fibroblast cultures derived from patients with well characterized and distinct OXPHOS defects. Mitochondrial membrane potential determination revealed a tendency to decrease in 5 patients' cells but reached statistical significance only in 2 of them. The remaining cells showed either no change or a slight increase in this parameter. Colocalization analysis of mitochondria and autophagosomes failed to show evidence of increased selective elimination of mitochondria but revealed more intense autophagosome staining in patients' fibroblasts compared with controls. Despite the absence of increased mitophagy, Parkin recruitment to mitochondria was detected in both controls' and patients' cells and was slightly higher in cells harboring complex I defects. Western blot analysis of the autophagosome marker LC3B, confirmed significantly higher levels of the protein bound to autophagosomes, LC3B-II, in patients' cells, suggesting an increased bulk autophagy in OXPHOS defective fibroblasts. Inhibition of lysosomal proteases caused significant accumulation of LC3B-II in control cells, whereas in patients' cells this phenomenon was less pronounced. Electron microscopy studies showed higher content of late autophagic vacuoles and lysosomes in OXPHOS defective cells, accompanied by higher levels of the lysosomal marker LAMP-1. Our findings suggest that in OXPHOS deficient fibroblasts autophagic flux could be partially hampered leading to an accumulation of autophagic vacuoles and lysosomesThis work was supported by grants PS09/01359, PI12/ 01683, PI11/00182 and CP11/00151 from Instituto de Salud Carlos III- Ministerio de Industria y Competitividad de España (ISCIIIMINECO, Spain), S2010/BMD-2361 and S2010/BMD-2402 from Comunidad de Madrid (CAM, Spain). AD is recipient of a research contract from ISCIII-MINECO (PI12/01683). MM is supported by a research contract ‘Miguel Servet’ ISCIII-MINECO (CP11/00151). AB is supported by a research contract (CIBERER-Spain)ElsevierDepartamento de Biología MolecularFacultad de Ciencias20142014-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/670426https://dx.doi.org/10.1016/j.bbadis.2014.03.013reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6704262026-06-23T12:46:27Z
dc.title.none.fl_str_mv Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
title Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
spellingShingle Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
Morán, María
Autophagosome
Autophagy
Lysosome
Mitophagy
OXPHOS deficiency
Parkin
Biología y Biomedicina / Biología
title_short Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
title_full Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
title_fullStr Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
title_full_unstemmed Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
title_sort Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease
dc.creator.none.fl_str_mv Morán, María
Delmiro, Aitor
Blázquez, Alberto
Ugalde, Cristina
Arenas, Joaquín
Martín, Miguel A.
author Morán, María
author_facet Morán, María
Delmiro, Aitor
Blázquez, Alberto
Ugalde, Cristina
Arenas, Joaquín
Martín, Miguel A.
author_role author
author2 Delmiro, Aitor
Blázquez, Alberto
Ugalde, Cristina
Arenas, Joaquín
Martín, Miguel A.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biología Molecular
Facultad de Ciencias
dc.subject.none.fl_str_mv Autophagosome
Autophagy
Lysosome
Mitophagy
OXPHOS deficiency
Parkin
Biología y Biomedicina / Biología
topic Autophagosome
Autophagy
Lysosome
Mitophagy
OXPHOS deficiency
Parkin
Biología y Biomedicina / Biología
description Oxidative phosphorylation system (OXPHOS) deficiencies are rare diseases but constitute the most frequent inborn errors of metabolism. We analyzed the autophagy route in 11 skin fibroblast cultures derived from patients with well characterized and distinct OXPHOS defects. Mitochondrial membrane potential determination revealed a tendency to decrease in 5 patients' cells but reached statistical significance only in 2 of them. The remaining cells showed either no change or a slight increase in this parameter. Colocalization analysis of mitochondria and autophagosomes failed to show evidence of increased selective elimination of mitochondria but revealed more intense autophagosome staining in patients' fibroblasts compared with controls. Despite the absence of increased mitophagy, Parkin recruitment to mitochondria was detected in both controls' and patients' cells and was slightly higher in cells harboring complex I defects. Western blot analysis of the autophagosome marker LC3B, confirmed significantly higher levels of the protein bound to autophagosomes, LC3B-II, in patients' cells, suggesting an increased bulk autophagy in OXPHOS defective fibroblasts. Inhibition of lysosomal proteases caused significant accumulation of LC3B-II in control cells, whereas in patients' cells this phenomenon was less pronounced. Electron microscopy studies showed higher content of late autophagic vacuoles and lysosomes in OXPHOS defective cells, accompanied by higher levels of the lysosomal marker LAMP-1. Our findings suggest that in OXPHOS deficient fibroblasts autophagic flux could be partially hampered leading to an accumulation of autophagic vacuoles and lysosomes
publishDate 2014
dc.date.none.fl_str_mv 2014
2014-01-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/670426
https://dx.doi.org/10.1016/j.bbadis.2014.03.013
url http://hdl.handle.net/10486/670426
https://dx.doi.org/10.1016/j.bbadis.2014.03.013
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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