Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome

Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mi...

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Autores: Villanueva-Paz, Marina, Povea-Cabello, Suleva, Villalón-García, Irene, Álvarez-Córdoba, Mónica, Suarez-Rivero, Juan M., Talaverón-Rey, Marta, Jackson, Sandra, Falcón-Moya, Rafael, Rodríguez-Moreno, Antonio, Sánchez-Alcázar, José Antonio
Tipo de recurso: artículo
Estado:Versión enviada para evaluación y publicación
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/222581
Acceso en línea:http://hdl.handle.net/10261/222581
Access Level:acceso abierto
Palabra clave:Mitochondria
Mitochondrial diseases
Autophagy
Mitophagy
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spelling Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndromeVillanueva-Paz, MarinaPovea-Cabello, SulevaVillalón-García, IreneÁlvarez-Córdoba, MónicaSuarez-Rivero, Juan M.Talaverón-Rey, MartaJackson, SandraFalcón-Moya, RafaelRodríguez-Moreno, AntonioSánchez-Alcázar, José AntonioMitochondriaMitochondrial diseasesAutophagyMitophagyMitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function. In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q10 (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells. To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ10 (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening.This work was supported by FIS PI16/00786 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Spanish Ministry of Education, Culture and Sports, “Ayudas para la Formación de Profesorado Universitario” (FPU) and AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).Peer reviewedElsevierInstituto de Salud Carlos IIIEuropean CommissionMinisterio de Educación, Cultura y Deporte (España)Asociación de Enfermos de Patologías Mitocondriales (España)Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro (España)Ministerio de Sanidad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Preprintinfo:eu-repo/semantics/submittedVersionhttp://hdl.handle.net/10261/222581reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1016/j.bbadis.2020.165726Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2225812026-05-22T06:33:51Z
dc.title.none.fl_str_mv Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
title Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
spellingShingle Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
Villanueva-Paz, Marina
Mitochondria
Mitochondrial diseases
Autophagy
Mitophagy
title_short Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
title_full Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
title_fullStr Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
title_full_unstemmed Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
title_sort Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
dc.creator.none.fl_str_mv Villanueva-Paz, Marina
Povea-Cabello, Suleva
Villalón-García, Irene
Álvarez-Córdoba, Mónica
Suarez-Rivero, Juan M.
Talaverón-Rey, Marta
Jackson, Sandra
Falcón-Moya, Rafael
Rodríguez-Moreno, Antonio
Sánchez-Alcázar, José Antonio
author Villanueva-Paz, Marina
author_facet Villanueva-Paz, Marina
Povea-Cabello, Suleva
Villalón-García, Irene
Álvarez-Córdoba, Mónica
Suarez-Rivero, Juan M.
Talaverón-Rey, Marta
Jackson, Sandra
Falcón-Moya, Rafael
Rodríguez-Moreno, Antonio
Sánchez-Alcázar, José Antonio
author_role author
author2 Povea-Cabello, Suleva
Villalón-García, Irene
Álvarez-Córdoba, Mónica
Suarez-Rivero, Juan M.
Talaverón-Rey, Marta
Jackson, Sandra
Falcón-Moya, Rafael
Rodríguez-Moreno, Antonio
Sánchez-Alcázar, José Antonio
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Ministerio de Educación, Cultura y Deporte (España)
Asociación de Enfermos de Patologías Mitocondriales (España)
Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro (España)
Ministerio de Sanidad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Mitochondria
Mitochondrial diseases
Autophagy
Mitophagy
topic Mitochondria
Mitochondrial diseases
Autophagy
Mitophagy
description Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function. In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q10 (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells. To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ10 (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Preprint
info:eu-repo/semantics/submittedVersion
format article
status_str submittedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/222581
url http://hdl.handle.net/10261/222581
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1016/j.bbadis.2020.165726
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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