microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases

Abstract Mitochondrial diseases due to mutations in the mitochondrial (mt) DNA are heterogeneous in clinical manifestations but usually include OXPHOS dysfunction. Mechanisms by which OXPHOS dysfunction contributes to the disease phenotype invoke, apart from cell energy deficit, maladaptive response...

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Autores principales:	Salvador Meseguer, Olga Boix, Carmen Navarro-González, Magda Villarroya, Rachid Boutoual, Sonia Emperador, Elena García-Arumí, Julio Montoya, M.-Eugenia Armengod
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8373d498e1a446ffb1debbb300c1e96f
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spelling	oai:doaj.org-article:8373d498e1a446ffb1debbb300c1e96f2021-12-02T16:06:33ZmicroRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases10.1038/s41598-017-06553-w2045-2322https://doaj.org/article/8373d498e1a446ffb1debbb300c1e96f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06553-whttps://doaj.org/toc/2045-2322Abstract Mitochondrial diseases due to mutations in the mitochondrial (mt) DNA are heterogeneous in clinical manifestations but usually include OXPHOS dysfunction. Mechanisms by which OXPHOS dysfunction contributes to the disease phenotype invoke, apart from cell energy deficit, maladaptive responses to mitochondria-to-nucleus retrograde signaling. Here we used five different cybrid models of mtDNA diseases to demonstrate that the expression of the nuclear-encoded mt-tRNA modification enzymes TRMU, GTPBP3 and MTO1 varies in response to specific pathological mtDNA mutations, thus altering the modification status of mt-tRNAs. Importantly, we demonstrated that the expression of TRMU, GTPBP3 and MTO1 is regulated by different miRNAs, which are induced by retrograde signals like ROS and Ca2+ via different pathways. Our data suggest that the up- or down-regulation of the mt-tRNA modification enzymes is part of a cellular response to cope with a stoichiometric imbalance between mtDNA- and nuclear-encoded OXPHOS subunits. However, this miRNA-mediated response fails to provide full protection from the OXPHOS dysfunction; rather, it appears to aggravate the phenotype since transfection of the mutant cybrids with miRNA antagonists improves the energetic state of the cells, which opens up options for new therapeutic approaches.Salvador MeseguerOlga BoixCarmen Navarro-GonzálezMagda VillarroyaRachid BoutoualSonia EmperadorElena García-ArumíJulio MontoyaM.-Eugenia ArmengodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Salvador Meseguer Olga Boix Carmen Navarro-González Magda Villarroya Rachid Boutoual Sonia Emperador Elena García-Arumí Julio Montoya M.-Eugenia Armengod microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
description	Abstract Mitochondrial diseases due to mutations in the mitochondrial (mt) DNA are heterogeneous in clinical manifestations but usually include OXPHOS dysfunction. Mechanisms by which OXPHOS dysfunction contributes to the disease phenotype invoke, apart from cell energy deficit, maladaptive responses to mitochondria-to-nucleus retrograde signaling. Here we used five different cybrid models of mtDNA diseases to demonstrate that the expression of the nuclear-encoded mt-tRNA modification enzymes TRMU, GTPBP3 and MTO1 varies in response to specific pathological mtDNA mutations, thus altering the modification status of mt-tRNAs. Importantly, we demonstrated that the expression of TRMU, GTPBP3 and MTO1 is regulated by different miRNAs, which are induced by retrograde signals like ROS and Ca2+ via different pathways. Our data suggest that the up- or down-regulation of the mt-tRNA modification enzymes is part of a cellular response to cope with a stoichiometric imbalance between mtDNA- and nuclear-encoded OXPHOS subunits. However, this miRNA-mediated response fails to provide full protection from the OXPHOS dysfunction; rather, it appears to aggravate the phenotype since transfection of the mutant cybrids with miRNA antagonists improves the energetic state of the cells, which opens up options for new therapeutic approaches.
format	article
author	Salvador Meseguer Olga Boix Carmen Navarro-González Magda Villarroya Rachid Boutoual Sonia Emperador Elena García-Arumí Julio Montoya M.-Eugenia Armengod
author_facet	Salvador Meseguer Olga Boix Carmen Navarro-González Magda Villarroya Rachid Boutoual Sonia Emperador Elena García-Arumí Julio Montoya M.-Eugenia Armengod
author_sort	Salvador Meseguer
title	microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
title_short	microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
title_full	microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
title_fullStr	microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
title_full_unstemmed	microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases
title_sort	microrna-mediated differential expression of trmu, gtpbp3 and mto1 in cell models of mitochondrial-dna diseases
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8373d498e1a446ffb1debbb300c1e96f
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microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases

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