Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism

Autores
Obis, Elia; Irazusta, Verónica Patricia; Sanchis, Daniel; Ros, Joaquim; Tamarit, Jordi
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of Frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVM) and shRNA interference. Using this approach, frataxin was reduced down to 5% to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs or the ATP/ADP ratio were comparable to controls. However, NRVM exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVM. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac specific treatment strategies for FRDA.
Fil: Obis, Elia. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Irazusta, Verónica Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta. Instituto de Investigación para la Industria Química (i); Argentina
Fil: Sanchis, Daniel. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Ros, Joaquim. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Tamarit, Jordi. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Materia
Friedreich Ataxia,
Mitochondria
Iron
Lipid Metabolism
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4751
Acceder
id CONICETDig_d9ad5ae437b3693109835f10d4be7e18
oai_identifier_str oai:ri.conicet.gov.ar:11336/4751
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolismObis, EliaIrazusta, Verónica PatriciaSanchis, DanielRos, JoaquimTamarit, JordiFriedreich Ataxia,MitochondriaIronLipid Metabolismhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of Frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVM) and shRNA interference. Using this approach, frataxin was reduced down to 5% to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs or the ATP/ADP ratio were comparable to controls. However, NRVM exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVM. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac specific treatment strategies for FRDA.Fil: Obis, Elia. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; EspañaFil: Irazusta, Verónica Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta. Instituto de Investigación para la Industria Química (i); ArgentinaFil: Sanchis, Daniel. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; EspañaFil: Ros, Joaquim. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; EspañaFil: Tamarit, Jordi. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; EspañaElsevier2014-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4751Obis, Elia; Irazusta, Verónica Patricia; Sanchis, Daniel; Ros, Joaquim; Tamarit, Jordi; Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism; Elsevier; Free Radical Biology and Medicine; 73; 8-2014; 21-330891-5849enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0891584914001853info:eu-repo/semantics/altIdentifier/doi/10.1016/j.freeradbiomed.2014.04.016info:eu-repo/semantics/altIdentifier/issn/0891-5849info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:23:20Zoai:ri.conicet.gov.ar:11336/4751instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:23:20.625CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
title Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
spellingShingle Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
Obis, Elia
Friedreich Ataxia,
Mitochondria
Iron
Lipid Metabolism
title_short Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
title_full Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
title_fullStr Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
title_full_unstemmed Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
title_sort Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism
dc.creator.none.fl_str_mv Obis, Elia
Irazusta, Verónica Patricia
Sanchis, Daniel
Ros, Joaquim
Tamarit, Jordi
author Obis, Elia
author_facet Obis, Elia
Irazusta, Verónica Patricia
Sanchis, Daniel
Ros, Joaquim
Tamarit, Jordi
author_role author
author2 Irazusta, Verónica Patricia
Sanchis, Daniel
Ros, Joaquim
Tamarit, Jordi
author2_role author
author
author
author
dc.subject.none.fl_str_mv Friedreich Ataxia,
Mitochondria
Iron
Lipid Metabolism
topic Friedreich Ataxia,
Mitochondria
Iron
Lipid Metabolism
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of Frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVM) and shRNA interference. Using this approach, frataxin was reduced down to 5% to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs or the ATP/ADP ratio were comparable to controls. However, NRVM exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVM. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac specific treatment strategies for FRDA.
Fil: Obis, Elia. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Irazusta, Verónica Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta. Instituto de Investigación para la Industria Química (i); Argentina
Fil: Sanchis, Daniel. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Ros, Joaquim. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
Fil: Tamarit, Jordi. Universitat de Leida. Departament de Ciències Mèdiques Bàsiques; España
description Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of Frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVM) and shRNA interference. Using this approach, frataxin was reduced down to 5% to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs or the ATP/ADP ratio were comparable to controls. However, NRVM exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVM. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac specific treatment strategies for FRDA.
publishDate 2014
dc.date.none.fl_str_mv 2014-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4751
Obis, Elia; Irazusta, Verónica Patricia; Sanchis, Daniel; Ros, Joaquim; Tamarit, Jordi; Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism; Elsevier; Free Radical Biology and Medicine; 73; 8-2014; 21-33
0891-5849
url http://hdl.handle.net/11336/4751
identifier_str_mv Obis, Elia; Irazusta, Verónica Patricia; Sanchis, Daniel; Ros, Joaquim; Tamarit, Jordi; Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism; Elsevier; Free Radical Biology and Medicine; 73; 8-2014; 21-33
0891-5849
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0891584914001853
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.freeradbiomed.2014.04.016
info:eu-repo/semantics/altIdentifier/issn/0891-5849
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.493442

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