Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons

This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine.

Detalles Bibliográficos
Autores: Galera‐Monge, Teresa, Zurita Díaz, Francisco, Canals, Isaac, Grønning Hansen, Marita, Rufián-Vázquez, Laura, Ehinger, Johannes K., Elmér, Eskil, Martín, Miguel A., Garesse, Rafael, Ahlenius, Henrik, Gallardo, M. Esther
Tipo de recurso: artículo
Estado:Versión publicada
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:10261/222289
Acceso en línea:http://hdl.handle.net/10261/222289
Access Level:acceso abierto
Palabra clave:Leigh syndrome
Mitochondrial disorders
Neuron
Disease modeling
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spelling Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neuronsGalera‐Monge, TeresaZurita Díaz, FranciscoCanals, IsaacGrønning Hansen, MaritaRufián-Vázquez, LauraEhinger, Johannes K.Elmér, EskilMartín, Miguel A.Garesse, RafaelAhlenius, HenrikGallardo, M. EstherLeigh syndromeMitochondrial disordersNeuronDisease modelingThis article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine.Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.This research was funded by ‘Fondo de Investigación Sanitaria, Instituto de Salud Carlos III co-funded by European Regional Development Funds’, grant number PI15/00484 and PI18/00151 to M.E.G; PI13/00556 and PI16/00789 to R.G. F.Z.-D. received grant support from the Ministerio de Educación, Cultura y Deporte (FPU13/00544). M.E.G. is supported by a ‘Miguel Servet’ contract (CP16/00046) from Instituto de Salud Carlos III and European Regional Development Funds. HA received support from the Swedish Research Council.Peer reviewedMultidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIMinisterio de Educación, Cultura y Deporte (España)Swedish Research CouncilEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/222289reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3390/ijms21093191Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2222892026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
title Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
spellingShingle Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
Galera‐Monge, Teresa
Leigh syndrome
Mitochondrial disorders
Neuron
Disease modeling
title_short Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
title_full Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
title_fullStr Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
title_full_unstemmed Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
title_sort Mitochondrial dysfunction and calcium dysregulation in Leigh syndrome induced pluripotent stem cell derived neurons
dc.creator.none.fl_str_mv Galera‐Monge, Teresa
Zurita Díaz, Francisco
Canals, Isaac
Grønning Hansen, Marita
Rufián-Vázquez, Laura
Ehinger, Johannes K.
Elmér, Eskil
Martín, Miguel A.
Garesse, Rafael
Ahlenius, Henrik
Gallardo, M. Esther
author Galera‐Monge, Teresa
author_facet Galera‐Monge, Teresa
Zurita Díaz, Francisco
Canals, Isaac
Grønning Hansen, Marita
Rufián-Vázquez, Laura
Ehinger, Johannes K.
Elmér, Eskil
Martín, Miguel A.
Garesse, Rafael
Ahlenius, Henrik
Gallardo, M. Esther
author_role author
author2 Zurita Díaz, Francisco
Canals, Isaac
Grønning Hansen, Marita
Rufián-Vázquez, Laura
Ehinger, Johannes K.
Elmér, Eskil
Martín, Miguel A.
Garesse, Rafael
Ahlenius, Henrik
Gallardo, M. Esther
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Educación, Cultura y Deporte (España)
Swedish Research Council
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Leigh syndrome
Mitochondrial disorders
Neuron
Disease modeling
topic Leigh syndrome
Mitochondrial disorders
Neuron
Disease modeling
description This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine.
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
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/222289
url http://hdl.handle.net/10261/222289
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3390/ijms21093191
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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 15,811543

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