Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.

TitleMitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.
Publication TypeJournal Article
Year of Publication2016
AuthorsLatorre-Pellicer, A, Moreno-Loshuertos, R, Lechuga-Vieco, AVictoria, Sánchez-Cabo, F, Torroja, C, Acín-Pérez, R, Calvo, E, Aix, E, González-Guerra, A, Logan, A, Bernad-Miana, MLuisa, Romanos, E, Cruz, R, Cogliati, S, Sobrino, B, Carracedo, Á, Pérez-Martos, A, Fernández-Silva, P, Ruíz-Cabello, J, Murphy, MP, Flores, I, Vázquez, J, Enríquez, JAntonio
JournalNature
Volume535
Issue7613
Pagination561-5
Date Published2016 07 28
ISSN1476-4687
KeywordsAging, Animals, Cell Nucleus, DNA, Mitochondrial, Female, Genetic Variation, Genome, Mitochondrial, Haplotypes, Insulin, Longevity, Male, Metabolism, Metabolomics, Mice, Mice, Congenic, Mitochondria, Mitochondrial Proteins, Obesity, Phenotype, Proteomics, Reactive Oxygen Species, Telomere Shortening, Transcriptome, Unfolded Protein Response
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.

DOI10.1038/nature18618
Alternate JournalNature
Citation Key10.1038/nature18618
PubMed ID27383793
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom