Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome

Defects in mitochondrial function lead to severe neuromuscular orphan pathologies known as mitochondrial disease. Among them, Leigh Syndrome is the most common pediatric presentation, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death. Mitochon...

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Autores: Gella, Alejandro, Prada-Dacasa, Patricia, Carrascal, Montserrat, Urpi, Andrea, González-Torres, Melania, Abián, Joaquín, Sanz, Elisenda, Quintana, Albert
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:10261/224024
Acceso en línea:http://hdl.handle.net/10261/224024
Access Level:acceso abierto
Palabra clave:Leigh syndrome
Animal models
Neuroscience
Proteomics
Cell type-specific
Mitochondrial isolation
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dc.title.none.fl_str_mv Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
title Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
spellingShingle Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
Gella, Alejandro
Leigh syndrome
Animal models
Neuroscience
Proteomics
Cell type-specific
Mitochondrial isolation
title_short Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
title_full Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
title_fullStr Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
title_full_unstemmed Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
title_sort Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome
dc.creator.none.fl_str_mv Gella, Alejandro
Prada-Dacasa, Patricia
Carrascal, Montserrat
Urpi, Andrea
González-Torres, Melania
Abián, Joaquín
Sanz, Elisenda
Quintana, Albert
author Gella, Alejandro
author_facet Gella, Alejandro
Prada-Dacasa, Patricia
Carrascal, Montserrat
Urpi, Andrea
González-Torres, Melania
Abián, Joaquín
Sanz, Elisenda
Quintana, Albert
author_role author
author2 Prada-Dacasa, Patricia
Carrascal, Montserrat
Urpi, Andrea
González-Torres, Melania
Abián, Joaquín
Sanz, Elisenda
Quintana, Albert
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas (España)
Universidad Autónoma de Barcelona
Instituto de Salud Carlos III
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Research Council
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Leigh syndrome
Animal models
Neuroscience
Proteomics
Cell type-specific
Mitochondrial isolation
topic Leigh syndrome
Animal models
Neuroscience
Proteomics
Cell type-specific
Mitochondrial isolation
description Defects in mitochondrial function lead to severe neuromuscular orphan pathologies known as mitochondrial disease. Among them, Leigh Syndrome is the most common pediatric presentation, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death. Mitochondrial diseases are characterized by a marked anatomical and cellular specificity. However, the molecular determinants for this susceptibility are currently unknown, hindering the efforts to find an effective treatment. Due to the complex crosstalk between mitochondria and their supporting cell, strategies to assess the underlying alterations in affected cell types in the context of mitochondrial dysfunction are critical. Here, we developed a novel virus-based tool, the AAV-mitoTag viral vector, to isolate mitochondria from genetically defined cell types. Expression of the AAV-mitoTag in the glutamatergic vestibular neurons of a mouse model of Leigh Syndrome lacking the complex I subunit Ndufs4 allowed us to assess the proteome and acetylome of a subset of susceptible neurons in a well characterized model recapitulating the human disease. Our results show a marked reduction of complex I N-module subunit abundance and an increase in the levels of the assembly factor NDUFA2. Transiently associated non-mitochondrial proteins such as PKCδ, and the complement subcomponent C1Q were also increased in Ndufs4-deficient mitochondria. Furthermore, lack of Ndufs4 induced ATP synthase complex and pyruvate dehydrogenase (PDH) subunit hyperacetylation, leading to decreased PDH activity. We provide novel insight on the pathways involved in mitochondrial disease, which could underlie potential therapeutic approaches for these pathologies.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
2020
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/224024
url http://hdl.handle.net/10261/224024
dc.language.none.fl_str_mv Inglés
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dc.publisher.none.fl_str_mv Frontiers Media
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spelling Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh SyndromeGella, AlejandroPrada-Dacasa, PatriciaCarrascal, MontserratUrpi, AndreaGonzález-Torres, MelaniaAbián, JoaquínSanz, ElisendaQuintana, AlbertLeigh syndromeAnimal modelsNeuroscienceProteomicsCell type-specificMitochondrial isolationDefects in mitochondrial function lead to severe neuromuscular orphan pathologies known as mitochondrial disease. Among them, Leigh Syndrome is the most common pediatric presentation, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death. Mitochondrial diseases are characterized by a marked anatomical and cellular specificity. However, the molecular determinants for this susceptibility are currently unknown, hindering the efforts to find an effective treatment. Due to the complex crosstalk between mitochondria and their supporting cell, strategies to assess the underlying alterations in affected cell types in the context of mitochondrial dysfunction are critical. Here, we developed a novel virus-based tool, the AAV-mitoTag viral vector, to isolate mitochondria from genetically defined cell types. Expression of the AAV-mitoTag in the glutamatergic vestibular neurons of a mouse model of Leigh Syndrome lacking the complex I subunit Ndufs4 allowed us to assess the proteome and acetylome of a subset of susceptible neurons in a well characterized model recapitulating the human disease. Our results show a marked reduction of complex I N-module subunit abundance and an increase in the levels of the assembly factor NDUFA2. Transiently associated non-mitochondrial proteins such as PKCδ, and the complement subcomponent C1Q were also increased in Ndufs4-deficient mitochondria. Furthermore, lack of Ndufs4 induced ATP synthase complex and pyruvate dehydrogenase (PDH) subunit hyperacetylation, leading to decreased PDH activity. We provide novel insight on the pathways involved in mitochondrial disease, which could underlie potential therapeutic approaches for these pathologies.This work was supported by a Marie Skłodowska-Curie COFUND action (H2020-MSCA-COFUND-2014-665919; AG), a Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2014-658352; ES), pre-doctoral fellowships (BES-2015-073041 to PP-D; 2018FI_B 00452 to AU), and a Ramón y Cajal fellowship (RyC-2012-11873; AQ). The Proteomics Laboratory CSIC/UAB is a member of Proteored, PRB3-ISCIII, and is supported by Grant PT17/0019/0008, funded by ISCIII and FEDER. ES received funds from MICIU Proyectos I+D+i “Retos Investigacion” (RTI2018-101838-J-I00). AQ received funds from the European Research Council (Starting grant NEUROMITO, ERC-2014-StG-638106), MINECO Proyectos I+D de Excelencia (SAF2014-57981P and SAF2017-88108-R), and AGAUR (2017SGR-323).Frontiers MediaEuropean CommissionMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas (España)Universidad Autónoma de BarcelonaInstituto de Salud Carlos IIIMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European Research CouncilGeneralitat de CatalunyaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/224024reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/665919info:eu-repo/grantAgreement/EC/H2020/658352info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-57981-Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-101838-J-I00RTI2018-101838-J-I00/AEI/10.13039/501100011033info:eu-repo/grantAgreement/EC/H2020/638106info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-57981Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-88108-RSAF2017-88108-R/AEI/10.13039/501100011033http://dx.doi.org/10.3389/fcell.2020.00660Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2240242026-05-22T06:33:51Z
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