Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

Lechuga-Vieco, Ana Victoria; Latorre-Pellicer, Ana; Calvo, Enrique; Torroja, Carlos; Pellico, Juan; Acin-Perez, Rebeca; García-Gil, María Luisa; Santos, Arnoldo; Bagwan, Navratan; Bonzon-Kulichenko, Elena; Magni, Ricardo; Benito, Marina; Justo-Méndez, Raquel; Simon, Anna Katharina; Sanchez-Cabo, Fatima; Vazquez, Jesus; Ruíz-Cabello, Jesús; Enriquez, Jose Antonio

Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can...

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Detalles Bibliográficos
Autores:	Lechuga-Vieco, Ana Victoria, Latorre-Pellicer, Ana, Calvo, Enrique, Torroja, Carlos, Pellico, Juan, Acin-Perez, Rebeca, García-Gil, María Luisa, Santos, Arnoldo, Bagwan, Navratan, Bonzon-Kulichenko, Elena, Magni, Ricardo, Benito, Marina, Justo-Méndez, Raquel, Simon, Anna Katharina, Sanchez-Cabo, Fatima, Vazquez, Jesus, Ruíz-Cabello, Jesús, Enriquez, Jose Antonio
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/15225
Acceso en línea:	http://hdl.handle.net/20.500.12105/15225
Access Level:	acceso abierto
Palabra clave:	Frailty Heart Diseases Hypertension, Pulmonary Adult Animals DNA, Mitochondrial Heteroplasmy Humans Mice Mitochondria

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spelling	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.Lechuga-Vieco, Ana VictoriaLatorre-Pellicer, AnaCalvo, EnriqueTorroja, CarlosPellico, JuanAcin-Perez, RebecaGarcía-Gil, María LuisaSantos, ArnoldoBagwan, NavratanBonzon-Kulichenko, ElenaMagni, RicardoBenito, MarinaJusto-Méndez, RaquelSimon, Anna KatharinaSanchez-Cabo, FatimaVazquez, JesusRuíz-Cabello, JesúsEnriquez, Jose AntonioFrailtyHeart DiseasesHypertension, PulmonaryAdultAnimalsDNA, MitochondrialHeteroplasmyHumansMiceMitochondriaIn most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.American Heart Association (AHA)Ministerio de Ciencia e Innovación (España)European Molecular Biology OrganizationHumand Frontier Science ProgramMinisterio de Economía, Industria y Competitividad (España)Programa Red Guipuzcoana de Ciencia, Tecnología e InformaciónBasque Government (España)ELKARTEK ProgramFundación BBVAMinisterio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu. (España)Unión Europea. Comisión Europea. H2020Marie CurieFundación La Marató TV3Fundación La CaixaInstituto de Salud Carlos IIIFundación ProCNICMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Agencia Estatal de Investigación (España)20222022-11-2420222022-04-0520222022-04-05journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15225reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme ALTF115-2019open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/152252026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
title	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
spellingShingle	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty. Lechuga-Vieco, Ana Victoria Frailty Heart Diseases Hypertension, Pulmonary Adult Animals DNA, Mitochondrial Heteroplasmy Humans Mice Mitochondria
title_short	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
title_full	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
title_fullStr	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
title_full_unstemmed	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
title_sort	Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
dc.creator.none.fl_str_mv	Lechuga-Vieco, Ana Victoria Latorre-Pellicer, Ana Calvo, Enrique Torroja, Carlos Pellico, Juan Acin-Perez, Rebeca García-Gil, María Luisa Santos, Arnoldo Bagwan, Navratan Bonzon-Kulichenko, Elena Magni, Ricardo Benito, Marina Justo-Méndez, Raquel Simon, Anna Katharina Sanchez-Cabo, Fatima Vazquez, Jesus Ruíz-Cabello, Jesús Enriquez, Jose Antonio
author	Lechuga-Vieco, Ana Victoria
author_facet	Lechuga-Vieco, Ana Victoria Latorre-Pellicer, Ana Calvo, Enrique Torroja, Carlos Pellico, Juan Acin-Perez, Rebeca García-Gil, María Luisa Santos, Arnoldo Bagwan, Navratan Bonzon-Kulichenko, Elena Magni, Ricardo Benito, Marina Justo-Méndez, Raquel Simon, Anna Katharina Sanchez-Cabo, Fatima Vazquez, Jesus Ruíz-Cabello, Jesús Enriquez, Jose Antonio
author_role	author
author2	Latorre-Pellicer, Ana Calvo, Enrique Torroja, Carlos Pellico, Juan Acin-Perez, Rebeca García-Gil, María Luisa Santos, Arnoldo Bagwan, Navratan Bonzon-Kulichenko, Elena Magni, Ricardo Benito, Marina Justo-Méndez, Raquel Simon, Anna Katharina Sanchez-Cabo, Fatima Vazquez, Jesus Ruíz-Cabello, Jesús Enriquez, Jose Antonio
author2_role	author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Ministerio de Ciencia e Innovación (España) European Molecular Biology Organization Humand Frontier Science Program Ministerio de Economía, Industria y Competitividad (España) Programa Red Guipuzcoana de Ciencia, Tecnología e Información Basque Government (España) ELKARTEK Program Fundación BBVA Ministerio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu. (España) Unión Europea. Comisión Europea. H2020 Marie Curie Fundación La Marató TV3 Fundación La Caixa Instituto de Salud Carlos III Fundación ProCNIC Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) Agencia Estatal de Investigación (España)
dc.subject.none.fl_str_mv	Frailty Heart Diseases Hypertension, Pulmonary Adult Animals DNA, Mitochondrial Heteroplasmy Humans Mice Mitochondria
topic	Frailty Heart Diseases Hypertension, Pulmonary Adult Animals DNA, Mitochondrial Heteroplasmy Humans Mice Mitochondria
description	In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-11-24 2022 2022-04-05 2022 2022-04-05
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/15225
url	http://hdl.handle.net/20.500.12105/15225
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme ALTF115-2019
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	American Heart Association (AHA)
publisher.none.fl_str_mv	American Heart Association (AHA)
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

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