Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons

The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies,...

Full description

Bibliographic Details
Authors: Boczonadi, Veronika, Meyer, Kathrin, Gonczarowska-Jorge, Humberto, Griffin, Helen, Roos, Andreas, Bartsakoulia, Marina, Bansagi, Boglarka, Ricci, Giulia, Palinkas, Fanni, Zahedi, René P., Bruni, Francesco, Kaspar, Brian, Lochmüller, Hanns, Boycott, Kym M., Müller, Juliane, Horvath, Rita
Format: article
Status:Published version
Publication Date:2018
Country:España
Institution:Universitat Pompeu Fabra
Repository:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/42907
Online Access:http://hdl.handle.net/10230/42907
http://dx.doi.org/10.1093/hmg/ddy127
Access Level:Open access
Keyword:Mutation
Mitochondria
Glycine-trna ligase
Mice
id ES_fe30d01cff129345cd8e7889d2f8fc64
oai_identifier_str oai:repositori.upf.edu:10230/42907
network_acronym_str ES
network_name_str España
repository_id_str
spelling Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neuronsBoczonadi, VeronikaMeyer, KathrinGonczarowska-Jorge, HumbertoGriffin, HelenRoos, AndreasBartsakoulia, MarinaBansagi, BoglarkaRicci, GiuliaPalinkas, FanniZahedi, René P.Bruni, FrancescoKaspar, BrianLochmüller, HannsBoycott, Kym M.Müller, JulianeHorvath, RitaMutationMitochondriaGlycine-trna ligaseMiceThe nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-onset disorders affecting skeletal muscle and heart. The downstream events explaining tissue-specific phenotype-genotype relations remained unclear. We investigated the mitochondrial function of GARS in human cell lines and in the GarsC210R mouse model. Human-induced neuronal progenitor cells (iNPCs) carrying dominant and recessive GARS mutations showed alterations of mitochondrial proteins, which were more prominent in iNPCs with dominant, neuropathy-causing mutations. Although comparative proteomic analysis of iNPCs showed significant changes in mitochondrial respiratory chain complex subunits, assembly genes, Krebs cycle enzymes and transport proteins in both recessive and dominant mutations, proteins involved in fatty acid oxidation were only altered by recessive mutations causing mitochondrial cardiomyopathy. In contrast, significant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms leading to neuropathy in this condition.R.H. is a Wellcome Investigator (109915/Z/15/Z) supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548) and the Mitochondrial European Educational Training (MEET), ITN MARIE CURIE PEOPLE, (317433). H.L. receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 305444 (RD-Connect), 305121 (Neuromics), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). H.J.G., A.R. and R.P.Z. acknowledge the financial support by the Ministeriumfür Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the SenatsverwaltungfürWirtschaft, Technologie und Forschung des Landes Berlin, and the BundesministeriumfürBildung und Forschung. H.G.J. further thanks the CAPES Foundation for financial support.Oxford University Press201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/42907http://dx.doi.org/10.1093/hmg/ddy127reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraCatalánHum Mol Genet. 2018; 27(12):2187-2204info:eu-repo/grantAgreement/EC/FP7/309548info:eu-repo/grantAgreement/EC/FP7/305444info:eu-repo/grantAgreement/EC/FP7/305121© The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/429072026-06-12T07:21:37Z
dc.title.none.fl_str_mv Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
title Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
spellingShingle Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
Boczonadi, Veronika
Mutation
Mitochondria
Glycine-trna ligase
Mice
title_short Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
title_full Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
title_fullStr Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
title_full_unstemmed Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
title_sort Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
dc.creator.none.fl_str_mv Boczonadi, Veronika
Meyer, Kathrin
Gonczarowska-Jorge, Humberto
Griffin, Helen
Roos, Andreas
Bartsakoulia, Marina
Bansagi, Boglarka
Ricci, Giulia
Palinkas, Fanni
Zahedi, René P.
Bruni, Francesco
Kaspar, Brian
Lochmüller, Hanns
Boycott, Kym M.
Müller, Juliane
Horvath, Rita
author Boczonadi, Veronika
author_facet Boczonadi, Veronika
Meyer, Kathrin
Gonczarowska-Jorge, Humberto
Griffin, Helen
Roos, Andreas
Bartsakoulia, Marina
Bansagi, Boglarka
Ricci, Giulia
Palinkas, Fanni
Zahedi, René P.
Bruni, Francesco
Kaspar, Brian
Lochmüller, Hanns
Boycott, Kym M.
Müller, Juliane
Horvath, Rita
author_role author
author2 Meyer, Kathrin
Gonczarowska-Jorge, Humberto
Griffin, Helen
Roos, Andreas
Bartsakoulia, Marina
Bansagi, Boglarka
Ricci, Giulia
Palinkas, Fanni
Zahedi, René P.
Bruni, Francesco
Kaspar, Brian
Lochmüller, Hanns
Boycott, Kym M.
Müller, Juliane
Horvath, Rita
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mutation
Mitochondria
Glycine-trna ligase
Mice
topic Mutation
Mitochondria
Glycine-trna ligase
Mice
description The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-onset disorders affecting skeletal muscle and heart. The downstream events explaining tissue-specific phenotype-genotype relations remained unclear. We investigated the mitochondrial function of GARS in human cell lines and in the GarsC210R mouse model. Human-induced neuronal progenitor cells (iNPCs) carrying dominant and recessive GARS mutations showed alterations of mitochondrial proteins, which were more prominent in iNPCs with dominant, neuropathy-causing mutations. Although comparative proteomic analysis of iNPCs showed significant changes in mitochondrial respiratory chain complex subunits, assembly genes, Krebs cycle enzymes and transport proteins in both recessive and dominant mutations, proteins involved in fatty acid oxidation were only altered by recessive mutations causing mitochondrial cardiomyopathy. In contrast, significant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms leading to neuropathy in this condition.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/42907
http://dx.doi.org/10.1093/hmg/ddy127
url http://hdl.handle.net/10230/42907
http://dx.doi.org/10.1093/hmg/ddy127
dc.language.none.fl_str_mv Catalán
language_invalid_str_mv Catalán
dc.relation.none.fl_str_mv Hum Mol Genet. 2018; 27(12):2187-2204
info:eu-repo/grantAgreement/EC/FP7/309548
info:eu-repo/grantAgreement/EC/FP7/305444
info:eu-repo/grantAgreement/EC/FP7/305121
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425662195924992
score 15,812429

Similar Items