Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing

Latorre-Pellicer, A. ; Moreno-Loshuertos, R. (Universidad de Zaragoza) ; Lechuga-Vieco, A. ; Sánchez-Cabo, F. ; Torroja, C. ; Acín-Pérez, R. ; Calvo, E. ; Aix, E. ; González-Guerra, A. ; Logan, A. ; Bernad-Miana, M. ; Romanos, E. ; Cruz, R. ; Cogliati, S. ; Sobrino, B. ; Carracedo, Á. ; Pérez-Martos, A. ; Fernández-Silva, P. (Universidad de Zaragoza) ; Ruíz-Cabello, J. ; Murphy, M.P. ; Flores, I. ; Vázquez, J. ; Enríquez, J.A. (Universidad de Zaragoza)

Resumen: Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability1. Many studies suggest that mtDNA variants may be associated with ageing or diseases2, 3, 4, although mechanistic evidence at the molecular level is lacking5, 6. 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 animals7, 8, 9 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.

Idioma: Inglés

DOI: 10.1038/nature18618

Año: 2016

Publicado en: Nature 535 (2016), 561-565
ISSN: 0028-0836

Factor impacto JCR: 40.137 (2016)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 1 / 63 = 0.016 (2016) - Q1 - T1

Factor impacto SCIMAGO: 18.388 - Multidisciplinary (Q1)

Tipo y forma: (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)