Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Lechuga-Vieco, Ana V.; Latorre-Pellicer, Ana; Johnston, Iain G.; Prota, Gennaro; Gileadi, Uzi; Justo-Méndez, Raquel; Acín-Pérez, Rebeca; Martínez-De-Mena, Raquel; Fernández-Toro, José María; Jimenez-Blasco, Daniel; Mora, Alfonso; Nicolás-Ávila, José A.; Santiago, Demetrio J.; Priori, Silvia G.; Bolaños, Juan P.; Sabio, Guadalupe; Criado, Luis M.; Ruiz-Cabello, Jesús; Cerundolo, Vincenzo; Jones, Nick S.; Enríquez, José Antonio

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specifi...

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Autores:	Lechuga-Vieco, Ana V., Latorre-Pellicer, Ana, Johnston, Iain G., Prota, Gennaro, Gileadi, Uzi, Justo-Méndez, Raquel, Acín-Pérez, Rebeca, Martínez-De-Mena, Raquel, Fernández-Toro, José María, Jimenez-Blasco, Daniel, Mora, Alfonso, Nicolás-Ávila, José A., Santiago, Demetrio J., Priori, Silvia G., Bolaños, Juan P., Sabio, Guadalupe, Criado, Luis M., Ruiz-Cabello, Jesús, Cerundolo, Vincenzo, Jones, Nick S., Enríquez, José Antonio
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2020
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/237993
Acceso en línea:	http://hdl.handle.net/10261/237993
Access Level:	acceso abierto

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network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
title	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
spellingShingle	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics Lechuga-Vieco, Ana V.
title_short	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
title_full	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
title_fullStr	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
title_full_unstemmed	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
title_sort	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics
dc.creator.none.fl_str_mv	Lechuga-Vieco, Ana V. Latorre-Pellicer, Ana Johnston, Iain G. Prota, Gennaro Gileadi, Uzi Justo-Méndez, Raquel Acín-Pérez, Rebeca Martínez-De-Mena, Raquel Fernández-Toro, José María Jimenez-Blasco, Daniel Mora, Alfonso Nicolás-Ávila, José A. Santiago, Demetrio J. Priori, Silvia G. Bolaños, Juan P. Sabio, Guadalupe Criado, Luis M. Ruiz-Cabello, Jesús Cerundolo, Vincenzo Jones, Nick S. Enríquez, José Antonio
author	Lechuga-Vieco, Ana V.
author_facet	Lechuga-Vieco, Ana V. Latorre-Pellicer, Ana Johnston, Iain G. Prota, Gennaro Gileadi, Uzi Justo-Méndez, Raquel Acín-Pérez, Rebeca Martínez-De-Mena, Raquel Fernández-Toro, José María Jimenez-Blasco, Daniel Mora, Alfonso Nicolás-Ávila, José A. Santiago, Demetrio J. Priori, Silvia G. Bolaños, Juan P. Sabio, Guadalupe Criado, Luis M. Ruiz-Cabello, Jesús Cerundolo, Vincenzo Jones, Nick S. Enríquez, José Antonio
author_role	author
author2	Latorre-Pellicer, Ana Johnston, Iain G. Prota, Gennaro Gileadi, Uzi Justo-Méndez, Raquel Acín-Pérez, Rebeca Martínez-De-Mena, Raquel Fernández-Toro, José María Jimenez-Blasco, Daniel Mora, Alfonso Nicolás-Ávila, José A. Santiago, Demetrio J. Priori, Silvia G. Bolaños, Juan P. Sabio, Guadalupe Criado, Luis M. Ruiz-Cabello, Jesús Cerundolo, Vincenzo Jones, Nick S. Enríquez, José Antonio
author2_role	author author author 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 Economía y Competitividad (España) Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Comunidad de Madrid European Commission Medical Research Council (UK) Cancer Research UK European Research Council Fundación BBVA Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description	Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.
publishDate	2020
dc.date.none.fl_str_mv	2020 2021 2021 2021
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/237993
url	http://hdl.handle.net/10261/237993
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
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dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv	American Association for the Advancement of Science
publisher.none.fl_str_mv	American Association for the Advancement of Science
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spelling	Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamicsLechuga-Vieco, Ana V.Latorre-Pellicer, AnaJohnston, Iain G.Prota, GennaroGileadi, UziJusto-Méndez, RaquelAcín-Pérez, RebecaMartínez-De-Mena, RaquelFernández-Toro, José MaríaJimenez-Blasco, DanielMora, AlfonsoNicolás-Ávila, José A.Santiago, Demetrio J.Priori, Silvia G.Bolaños, Juan P.Sabio, GuadalupeCriado, Luis M.Ruiz-Cabello, JesúsCerundolo, VincenzoJones, Nick S.Enríquez, José AntonioHeteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.This study was supported by MINECO SAF2015-65633-R to JAE, SAF2016-78114-R to J.P.B. and SAF2017- 84494-C2-1-R to J.R.-C. G.S. thanks MINECO-FEDER SAF2016-79126-R and Comunidad de Madrid IMMUNOTHERCAN-CM B2017/BMD-3733. N.S.J. thanks EP/N014529/1. CIBERFES (CB16/10/00282) to J.P.B. and J.A.E., and H2020 European Commission (BatCure grant 666918) to J.P.B. A.V.L.-V. was supported by SOFPI-fellowship from the MINECO. V.C. is supported by the UK Medical Research Council, Cancer Research UK (CRUK) (C399/A2291), and the Oxford Biomedical Research Centre. I.G.J. thanks the European Research Council (ERC- No. 805046-EvoConBiO). The CNIC is supported by MINECO and Pro-CNIC Foundation and is a SO-MINECO (award SEV-2015-0505). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (grant no. MDM-2017- 0720), ELKARTEK Program (grant no. KK-2019/bmG19), and BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018)American Association for the Advancement of ScienceMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Comunidad de MadridEuropean CommissionMedical Research Council (UK)Cancer Research UKEuropean Research CouncilFundación BBVAConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120202021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/237993reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65633-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-78114-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-84494-C2-1-RSAF2017-84494-C2-1-R/AEI/10.13039/501100011033info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-79126-R, B2017info:eu-repo/grantAgreement/EC/H2020/666918info:eu-repo/grantAgreement/EC/H2020/805046info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2015-0505info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2017-0720http://dx.doi.org/10.1126/sciadv.aba5345Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2379932026-05-22T06:33:51Z
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Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

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