Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations

PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson's disease (PRKN-PD) but have been only...

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Autores: González-Casacuberta, Ingrid, Juárez-Flores, Diana-Luz, Ezquerra, Mario, Fucho, Raquel, Catalán-García, Marc, Guitart-Mampel, Mariona, Tobías Rossell, Ester, García-Ruiz, Carmen, Fernández-Checa, José C., Tolosa, Eduardo, Martí, María-José, Grau-Junyent, Josep María, Fernández-Santiago, Rubén, Cardellach, Francesc, Morén, Constanza, Garrabou, Glòria
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/201629
Acceso en línea:http://hdl.handle.net/10261/201629
Access Level:acceso abierto
Palabra clave:Parkinson’s disease
Parkin mutation
Mitochondrial function
Autophagy
Fibroblasts
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spelling Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutationsGonzález-Casacuberta, IngridJuárez-Flores, Diana-LuzEzquerra, MarioFucho, RaquelCatalán-García, MarcGuitart-Mampel, MarionaTobías Rossell, EsterGarcía-Ruiz, CarmenFernández-Checa, José C.Tolosa, EduardoMartí, María-JoséGrau-Junyent, Josep MaríaFernández-Santiago, RubénCardellach, FrancescMorén, ConstanzaGarrabou, GlòriaParkinson’s diseaseParkin mutationMitochondrial functionAutophagyFibroblastsPRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson's disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing.We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions.In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions.The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.This work was supported by funds from Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (ISCIII) (grant number PI11/00462), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), initiatives of Instituto Carlos III (ISCIII) and FEDER, and Fundació Privada Cellex (CP042187).Impact JournalsInstituto de Salud Carlos IIICentro de Investigación Biomédica en Red Enfermedades Raras (España)European CommissionFundació Privada CellexConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/201629reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.18632/aging.102014Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2016292026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
title Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
spellingShingle Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
González-Casacuberta, Ingrid
Parkinson’s disease
Parkin mutation
Mitochondrial function
Autophagy
Fibroblasts
title_short Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
title_full Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
title_fullStr Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
title_full_unstemmed Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
title_sort Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations
dc.creator.none.fl_str_mv González-Casacuberta, Ingrid
Juárez-Flores, Diana-Luz
Ezquerra, Mario
Fucho, Raquel
Catalán-García, Marc
Guitart-Mampel, Mariona
Tobías Rossell, Ester
García-Ruiz, Carmen
Fernández-Checa, José C.
Tolosa, Eduardo
Martí, María-José
Grau-Junyent, Josep María
Fernández-Santiago, Rubén
Cardellach, Francesc
Morén, Constanza
Garrabou, Glòria
author González-Casacuberta, Ingrid
author_facet González-Casacuberta, Ingrid
Juárez-Flores, Diana-Luz
Ezquerra, Mario
Fucho, Raquel
Catalán-García, Marc
Guitart-Mampel, Mariona
Tobías Rossell, Ester
García-Ruiz, Carmen
Fernández-Checa, José C.
Tolosa, Eduardo
Martí, María-José
Grau-Junyent, Josep María
Fernández-Santiago, Rubén
Cardellach, Francesc
Morén, Constanza
Garrabou, Glòria
author_role author
author2 Juárez-Flores, Diana-Luz
Ezquerra, Mario
Fucho, Raquel
Catalán-García, Marc
Guitart-Mampel, Mariona
Tobías Rossell, Ester
García-Ruiz, Carmen
Fernández-Checa, José C.
Tolosa, Eduardo
Martí, María-José
Grau-Junyent, Josep María
Fernández-Santiago, Rubén
Cardellach, Francesc
Morén, Constanza
Garrabou, Glòria
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Centro de Investigación Biomédica en Red Enfermedades Raras (España)
European Commission
Fundació Privada Cellex
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Parkinson’s disease
Parkin mutation
Mitochondrial function
Autophagy
Fibroblasts
topic Parkinson’s disease
Parkin mutation
Mitochondrial function
Autophagy
Fibroblasts
description PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson's disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing.We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions.In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions.The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
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/10261/201629
url http://hdl.handle.net/10261/201629
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.18632/aging.102014
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
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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score 15,812429

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