학술논문
Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics.
Document Type
Academic Journal
Author
Lechuga-Vieco AV; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; CIBERES: C/ Melchor Fernández-Almagro 3, 28029 Madrid, Spain.; Latorre-Pellicer A; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, IIS Aragon, E-50009 Zaragoza, Spain.; Johnston IG; Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Bergen, Bergen, Norway.; Prota G; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; Gileadi U; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; Justo-Méndez R; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Acín-Pérez R; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Martínez-de-Mena R; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Fernández-Toro JM; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Jimenez-Blasco D; IBFG, Universidad de Salamanca, Salamanca, Spain.; IBSAL, Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, Salamanca, Spain.; CIBERFES, C/Melchor Fernández-Almagro 3, 28029 Madrid, Spain.; Mora A; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Nicolás-Ávila JA; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Santiago DJ; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Molecular Cardiology, IRCCS ICS Maugeri, Pavia, Italy.; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Priori SG; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Molecular Cardiology, IRCCS ICS Maugeri, Pavia, Italy.; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Bolaños JP; IBFG, Universidad de Salamanca, Salamanca, Spain.; IBSAL, Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, Salamanca, Spain.; CIBERFES, C/Melchor Fernández-Almagro 3, 28029 Madrid, Spain.; Sabio G; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Criado LM; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; Ruíz-Cabello J; CIBERES: C/ Melchor Fernández-Almagro 3, 28029 Madrid, Spain.; CIC biomaGUNE 20014 Donostia/San Sebastián, Gipuzkoa, Spain.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.; Universidad Complutense Madrid, Madrid, Spain.; Cerundolo V; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; Jones NS; EPSRC Centre for the Mathematics of Precision Healthcare, Department of Mathematics, Imperial College London, London SW7 2BB, UK.; Enríquez JA; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.; CIBERFES, C/Melchor Fernández-Almagro 3, 28029 Madrid, Spain.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: eCollection Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: PubMed not MEDLINE; MEDLINE
Subject
Language
English
Abstract
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.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)