title: Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.
abstract: Human mitochondrial DNA (mtDNA) shows extensive within population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic,metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation,insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.
authors.forename: Ana
authors.initials: A
authors.lastname: Latorre-Pellicer
authors.forename: Raquel
authors.initials: R
authors.lastname: Moreno-Loshuertos
authors.forename: Ana Victoria
authors.initials: AV
authors.lastname: Lechuga-Vieco
authors.forename: Fátima
authors.initials: F
authors.lastname: Sánchez-Cabo
authors.forename: Carlos
authors.initials: C
authors.lastname: Torroja
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.forename: Enrique
authors.initials: E
authors.lastname: Calvo
authors.forename: Esther
authors.initials: E
authors.lastname: Aix
authors.forename: Andrés
authors.initials: A
authors.lastname: González-Guerra
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Bernad-Miana
authors.forename: Eduardo
authors.initials: E
authors.lastname: Romanos
authors.forename: Raquel
authors.initials: R
authors.lastname: Cruz
authors.forename: Sara
authors.initials: S
authors.lastname: Cogliati
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sobrino
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.forename: Acisclo
authors.initials: A
authors.lastname: Pérez-Martos
authors.forename: Patricio
authors.initials: P
authors.lastname: Fernández-Silva
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruíz-Cabello
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Ignacio
authors.initials: I
authors.lastname: Flores
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Enríquez
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D054629:Genome, Mitochondrial / Q000235:genetics; D006239:Haplotypes; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D008660:Metabolism / Q000235:genetics* / Q000502:physiology; D055432:Metabolomics; D051379:Mice; D020297:Mice, Congenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D059506:Telomere Shortening; D059467:Transcriptome; D056811:Unfolded Protein Response
chemical_list: D004272:DNA, Mitochondrial; D007328:Insulin; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species