dc.contributor.author | Lechuga-Vieco, Ana Victoria | |
dc.contributor.author | Latorre-Pellicer, Ana | |
dc.contributor.author | Calvo, Enrique | |
dc.contributor.author | Torroja, Carlos | |
dc.contributor.author | Pellico, Juan | |
dc.contributor.author | Acin-Perez, Rebeca | |
dc.contributor.author | García-Gil, María Luisa | |
dc.contributor.author | Santos, Arnoldo | |
dc.contributor.author | Bagwan, Navratan | |
dc.contributor.author | Bonzon-Kulichenko, Elena | |
dc.contributor.author | Magni, Ricardo | |
dc.contributor.author | Benito, Marina | |
dc.contributor.author | Justo-Méndez, Raquel | |
dc.contributor.author | Simon, Anna Katharina | |
dc.contributor.author | Sanchez-Cabo, Fatima | |
dc.contributor.author | Vazquez, Jesus | |
dc.contributor.author | Ruíz-Cabello, Jesús | |
dc.contributor.author | Enriquez, Jose Antonio | |
dc.date.accessioned | 2022-11-24T08:20:22Z | |
dc.date.available | 2022-11-24T08:20:22Z | |
dc.date.issued | 2022-04-05 | |
dc.identifier.citation | Circulation . 2022 Apr 5;145(14):1084-1101. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15225 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | Dr Lechuga-Vieco was supported by a Predoctoral Fellowship from Ministerio
de Ciencia e Innovación (SVP-2013-068089) and by a Postdoctoral Fellowship
from the European Molecular Biology Organization (ALTF115-2019). This
study was supported by grants to Dr Enríquez from Ministerio de Ciencia e Innovación
(grants SAF2015-65633-R and RTI2018-099357-B-I00) and Humand
Frontier Science Program (grant RGP0016/2018). Dr Ruíz-Cabello is
supported by grants from the Ministerio de Economía, Industria y Competitivida
(grant SAF2017-84494-C2-R), Programa Red Guipuzcoana de Ciencia, Tecnología
e Información (grant 2018-CIEN-000058-01), and the Gobierno Vasco,
Dpto Industria, Innovación, Comercio y Turismo under the ELKARTEK Program
(grant KK-2019/bmG19). Dr Ruíz-Cabello received funding from the BBVA
Foundation (Ayudas a Equipos de Investigación Científica Biomedicina 2018).
CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program
from the Spanish State Research Agency (grant MDM-2017-0720). Dr
Santos has received funding from the European Union’s Horizon 2020 research
and innovation program under the Marie Sklodowska-Curie grant agreement
796721. Dr Vázquez received funding from Ministerio de Ciencia e Innovación
(grants PGC2018-097019-B-I00 and PRB3-IPT17/0019/0003-ISCIII-SGEFI/
ERDF, ProteoRed), the Fundació MaratóTV3 (grant 122/C/2015), and “la
Caixa” Banking Foundation (project code HR17-00247). The Centro Nacional
de Investigaciónes Cardiovasculares is supported by the Instituto de Salud Carlos
III, the Ministerio de Ciencia e Innovación, and the Pro Centro Nacional de
Investigaciónes Cardiovasculares Foundation and is a Severo Ochoa Center of
Excellence. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Heart Association (AHA) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Frailty | es_ES |
dc.subject.mesh | Heart Diseases | es_ES |
dc.subject.mesh | Hypertension, Pulmonary | es_ES |
dc.subject.mesh | Adult | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | DNA, Mitochondrial | es_ES |
dc.subject.mesh | Heteroplasmy | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Mitochondria | es_ES |
dc.title | Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 35236094 | es_ES |
dc.format.volume | 145 | es_ES |
dc.format.number | 14 | es_ES |
dc.format.page | 1084 | es_ES |
dc.identifier.doi | 10.1161/CIRCULATIONAHA.121.056286 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | European Molecular Biology Organization | es_ES |
dc.contributor.funder | Humand Frontier Science Program | es_ES |
dc.contributor.funder | Ministerio de Economía, Industria y Competitividad (España) | es_ES |
dc.contributor.funder | Programa Red Guipuzcoana de Ciencia, Tecnología e Información | es_ES |
dc.contributor.funder | Basque Government (España) | es_ES |
dc.contributor.funder | ELKARTEK Program | es_ES |
dc.contributor.funder | Fundación BBVA | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu. (España) | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. H2020 | es_ES |
dc.contributor.funder | Marie Curie | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1524-4539 | es_ES |
dc.relation.publisherversion | doi: 10.1161/CIRCULATIONAHA.121.056286. | es_ES |
dc.identifier.journal | Circulation | es_ES |
dc.repisalud.orgCNIC | CNIC::Unidades técnicas::Proteómica | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/ALTF115-2019 | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SVP-2013-068089 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SAF2015-65633-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RTI2018-099357-B-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RGP0016/2018 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SAF2017-84494-C2-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/2018-CIEN-000058-01 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/KK-2019/bmG19 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MDM-2017-0720 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PGC2018-097019-B-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PRB3-IPT17/0019/0003-ISCIII-SGEFI | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/122/C/2015 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/HR17-00247 | es_ES |