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Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy

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dc.contributor.authorLatorre-Pellicer, Ana
dc.contributor.authorLechuga-Vieco, Ana V.
dc.contributor.authorJohnston, Iain G
dc.contributor.authorHämäläinen, Riikka H
dc.contributor.authorPellico, Juan
dc.contributor.authorJusto-Mendez, Raquel
dc.contributor.authorFernandez-Toro, Jose Maria
dc.contributor.authorClaveria, Cristina
dc.contributor.authorGuaras, Adela
dc.contributor.authorSierra, Rocio
dc.contributor.authorLlop, Jordi
dc.contributor.authorTorres, Miguel
dc.contributor.authorCriado-Rodriguez, Luis M.
dc.contributor.authorSuomalainen, Anu
dc.contributor.authorJones, Nick S
dc.contributor.authorRuiz-Cabello, Jesus
dc.contributor.authorEnriquez, Jose Antonio
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderFundación ProCNIC
dc.contributor.funderCentro de Investigación Biomedica en Red - CIBER
dc.contributor.funderUnión Europea. Comisión Europea
dc.date.accessioned2020-01-14T14:31:51Z
dc.date.available2020-01-14T14:31:51Z
dc.date.issued2019-12-03
dc.description.abstractmtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipA.V.L.-V. was supported by fellowship SVP-2013-068089 from MCIU. I.G.J. thanks ERC StG EvoConBiO, and a Turing fellowship from the Alan Turing Institute. N.J. thanks EP/N014529/1. SAF2017-84494-C2-R and Programa Red Guipuzcoana de Ciencia, Tecnologıa e Informacion 2018-CIEN-000058-01, and the Basque Government under its ELKARTEK research program (ref: KK-2019/00015) to J.R.-C. The work at CIC biomaGUNE was performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency – Grant No. MDM-2017-0720. This study was supported by grants from the MCNU (SAF2015-65633-R), the EU (UE0/MCA317433), the Biomedical ResearchNetworking Center on Frailty and Healthy Ageing (CIBERFES-ISCiii), and the HFSP agency (RGP0016/2018) to J.A.E. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). AGRADECIENTOS: ProCNIC; Severo Ochoa (SEV-2015-0505)es_ES
dc.format.number6es_ES
dc.format.page1120-1130.e5es_ES
dc.format.volume30es_ES
dc.identifier.citationCell Metab. 2019; 30(6):1120-30es_ES
dc.identifier.doi10.1016/j.cmet.2019.09.007es_ES
dc.identifier.e-issn1932-7420es_ES
dc.identifier.issn1550-4131es_ES
dc.identifier.journalCell metabolismes_ES
dc.identifier.pubmedID31588014es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8882
dc.language.isoenges_ES
dc.publisherCell Presses_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/MDM-2017-0720es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.cmet.2019.09.007es_ES
dc.repisalud.institucionCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Genética Funcional del Sistema de Fosforilación Oxidativaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Control Genético del Desarrollo y Regeneración de Órganoses_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Transgénesises_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectEmbryoes_ES
dc.subjectGermline selectiones_ES
dc.subjectHeteroplasmyes_ES
dc.subjectMitochondriaes_ES
dc.subjectMitochondrial replacementes_ES
dc.subjectmtDNA competitiones_ES
dc.subjectmtDNA inheritancees_ES
dc.titleRegulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmyes_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
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