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LETTER Doi:10.1038/Nature18618 LETTER doi:10.1038/nature18618 Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing Ana Latorre-Pellicer1,2, Raquel Moreno-Loshuertos3, Ana Victoria Lechuga-Vieco1,4, Fátima Sánchez-Cabo1, Carlos Torroja1, Rebeca Acín-Pérez1, Enrique Calvo1, Esther Aix1, Andrés González-Guerra1, Angela Logan5, María Luisa Bernad-Miana6, Eduardo Romanos6, Raquel Cruz2, Sara Cogliati1, Beatriz Sobrino7, Ángel Carracedo2,7,8, Acisclo Pérez-Martos3, Patricio Fernández-Silva3, Jesús Ruíz-Cabello1,4,9, Michael P. Murphy5, Ignacio Flores1, Jesús Vázquez1 & José Antonio Enríquez1,3 Human mitochondrial DNA (mtDNA) shows extensive within- Extended Data Fig. 3a, b); including ovary preservation, with less lipo- population sequence variability1. Many studies suggest that fuscin accumulation at 12 months in BL/6NZB mice (Extended Data mtDNA variants may be associated with ageing or diseases2–4, Fig. 3e, f). Telomeres in one-year-old animals were on average approx- although mechanistic evidence at the molecular level is lacking5,6. imately 11% longer in BL/6C57 mice, whereas in two-year-old animals Mitochondrial replacement has the potential to prevent this was inverted, with BL/6NZB telomeres slightly longer (Fig. 1d). This transmission of disease-causing oocyte mtDNA and to improve is due to a BL/6C57 telomere-length-reduction rate that is double than fertility by ‘rejuvenating’ oocytes of sub-fertile or infertile women. that of BL/6NZB mice (Fig. 1e). Liver necropsy revealed a higher inci- However, extension of this technology requires a comprehensive dence of tumours in BL/6C57 mice at death (Fig. 1f and Extended Data understanding of the physiological relevance of mtDNA sequence Fig. 3c, d), suggesting greater genome instability. variability and its match with the nuclear-encoded mitochondrial Four days after birth, respiration and ATP synthesis were lower in genes. Studies in conplastic animals7–9 allow comparison of liver mitochondria from BL/6NZB mice. Both variables subsequently individuals with the same nuclear genome but different mtDNA equalized, but from 100-days-old onwards, the rates in BL/6C57 liver variants, and have provided both supporting and refuting evidence mitochondria decreased progressively (Fig. 1g). These changes were that mtDNA variation influences organismal physiology. However, due to a steady decline in BL/6C57 respiration, with BL/6NZB respiration most of these studies did not confirm the conplastic status, focused remaining constant between days 20 and 300 (Fig. 1h). Liver mtDNA on younger animals, and did not investigate the full range of sequencing revealed no age-related increase in mtDNA mutations in physiological and phenotypic variability likely to be influenced either mtDNA backgrounds (Extended Data Table 2, Supplementary by mitochondria. Here we systematically characterized conplastic Data1). Later metabolic deterioration, lower tumour incidence, mice throughout their lifespan using transcriptomic, proteomic, slower telomere attrition11, and sustained ovarian function indicate metabolomic, biochemical, physiological and phenotyping that the NZB mtDNA promotes healthier ageing in the BL/6 nuclear studies. We show that mtDNA haplotype profoundly influences background. mitochondrial proteostasis and reactive oxygen species generation, Gene expression signatures of 12-week-old mice (Fig. 2a and insulin signalling, obesity, and ageing parameters including Supplementary Data 2) revealed differences in molecular functions telomere shortening and mitochondrial dysfunction, resulting related to ‘lipid and carbohydrate metabolism’ in liver and heart and in profound differences in health longevity between conplastic ‘free radical scavenging’ specifically in liver (Fig. 2b). Consistent with strains. increased PPARα activity, BL/6NZB mice had higher expression of The mtDNAs of C57BL/6 and NZB/OlaHsd mice differ by 12 missense lipid metabolism and lower expression of carbohydrate metabolism mutations, 4 transfer RNA (tRNA) mutations, 8 ribosomal RNA and inflammation pathways (Extended Data Fig. 4 and Supplementary (rRNA) mutations, and 10 non-coding-region mutations (Extended Data 2). Data Fig. 1b, Extended Data Table 1 and Supplementary Data 1), a Plasma and liver metabolomics of 12–week-old mice confirm the level of divergence comparable to that between human Eurasian and mtDNA haplotype effect in three main groups: glutathione metabo- African mtDNAs. We developed a conplastic mouse strain (Extended lism; digestion and absorption; and lipid and membrane metabolism Data Fig. 1a) with the C57BL/6 nuclear genome and the NZB/OlaHsd (Fig. 2c, Extended Data Fig. 5 and Supplementary Data 3). Metabolite mtDNA, hereafter referred to as BL/6NZB. The original C57BL/6 strain set enrichment analysis (MSEA) of glutathione metabolism revealed with the C57BL/6 nuclear genome and C57BL/6 mitochondrial genome enhanced glutathione turnover12 and reactive oxygen species (ROS) is hereafter referred to as BL/6C57 . Nuclear genome purity was con- defence in BL/6NZB animals (Fig. 2d and Extended Data Fig. 5b). In firmed (Extended Data Fig. 1c–e). Conplastic animals, BL/6C57 and parallel, we detected lower levels of the hepatic lipid peroxidation BL/6NZB, were fertile, and on a chow diet there were no weight dif- product 12,13-hydroxyoctadec-9(Z)-enoate. Other affected metab- ferences throughout the growth period (Extended Data Fig. 2a, b), olites included a number of fatty acids and lysophospholipids, con- with marginal differences in activity observed in metabolic chambers sistent with the differences in membrane metabolism (Extended Data (Extended Data Fig. 2c–e). Fig. 5d). Unexpectedly BL/6NZB extended median lifespan by 16% without Quantitative proteomics revealed a differential profile for the ROS modifying maximum lifespan (Fig. 1a). After 9 months, BL/6NZB mice defence proteome (Fig. 2e, f and Supplementary Data 4). In liver, gained less weight (Fig. 1b). Two-year-old BL/6C57 animals mani- the major mitochondria-located redox regulators Glrx2, Glrx5 and fested more signs of ageing10 than age-matched BL/6NZB mice (Fig. 1c, Txnrd2 were increased in young and old BL/6NZB mice, whereas 1Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain. 2Grupo de Medicina Xenómica, CIBERER, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. 3Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza 50009, Spain. 4CIBERES, C/ Melchor Fernández-Almagro 3, 28029 Madrid, Spain. 5Medical Research Council Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. 6SAI de Biomedicina y Biomateriales & Phenotypic Unit, Instituto Aragonés de Ciencias de la salud, Zaragoza 50009, Spain. 7Fundación Pública Gallega Medicina Xenómica, SERGAS, Complexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain. 8Center of Excellence in Genomic Medicine Research, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. 9Universidad Complutense de Madrid, Madrid 28606, Spain. 00 MONTH 2016 | VOL 000 | NATURE | 1 RESEARCH LETTER 1-year-old 2-year-old ab40 c d 6 100 * * ** *** C57 *** * * * * 15 BL/6 * 4 35 * BL/6C57 * 75 ** NZB 2 BL/6 10 50 * 30 0 887 NZB 741 Weight (g) BL/6 *** 4 C57 5 25 BL/6 25 Frequency (%) Per cent survival BL/6NZB 2 Ageing score (a.u.) 0 20 0 0 0 50 100 150 200 250 300 350 400 0200 400600 800 1,000 1,200 0200 400600 800 BL/6C57 BL/6NZB Age (days) Age (days) Telomere length (a.u.) e fgTumour No tumour Pyr + malGlu + malSuccinate h 0.5 –1 20 nmol O2 min per mg protein 25 300 BL/6C57 glu + mal C57 0.0 BL/6 pyr + mal 20 15 ** ]) 10 1001,000 C57 200 6 15 * –0.5 nmol ATP min–1 per mg protein 10 0.5 per mg protein ]/[BL/ –1 Counts n 10 NZB 100 mi 0.0 2 5 O BL/6NZB glu + mal 5 10 100 1,000 log([BL/6 BL/6NZB pyr + mal nmol Telomere length reduction (%) –0.5 0 0 0 4 21 65 115 280 680 110100 BL/6C57 BL/6NZB BL/6C57 BL/6NZB Age (days) Age (weeks) Figure 1 | Conplastic animals differ in metabolism and ageing profiles. rank sum test). e, Telomere length reduction during second year of life a, Survival curves (n = 31 per genotype (19 males, 12 females); Gehan– (mean ± s.e.m. *P < 0.05, two-tailed t-test). f, Tumour incidence in Breslow–Wilcoxon test *P < 0.05). b, Weight gain (chow diet, n = 19 males animals dying from natural causes (n = 14 for BL/6NZB, n = 20 for BL/6C57; per genotype, mean ± s.e.m., *P < 0.05, two-tailed t-test). c, Mice that were **P < 0.01, Fisher’s exact test). g, Relative O2 consumption (coupled) ~2 years old were scored for ageing parameters (n = 5 for BL/6NZB, n = 4 and ATP synthesis rates in liver mitochondria (n = 4 per genotype and C57 for BL/6 ). For more information on ageing parameters see Extended age; mean ± s.d.). h, O2 consumption (coupled) respiration in liver Data Fig. 3a. a.u., arbitrary units. d, Telomere length in hair follicle cells mitochondria simultaneously isolated from 22-, 30-, 120- and 300-day-old of 1- (n = 6 per group) and 2-year-old mice (n = 5 for BL/6NZB, n = 4 males (n = 8). for BL/6C57). Red lines indicate mean length (***P < 0.001, Wilcoxon’s abLiver Liver and heart c –log10 (BH P) PLSD-DA 0 1.0 4 Liver BL/6C57 Liver BL/6NZB Plasma BL/6C57 Plasma BL/6NZB Liver BL/6NZB H.BL/6NZB vs BL/6C57 Liver and plasma (197) Liver (313) Plasma (287) 0.5 } Heart BL/6C57 L.BL/6NZB vs BL/6C57 10 10 5 ) t r s s e n g 5 5 0.0 m 0 Heart BL/6NZB 0 0 -variate 2 (30, 25, 5 Cell cycl –0.5 X –5 –5 –5 Liver BL/6C57 Cell signalling Leading logFC dim 2 –10 Cell morphology Gene expressio Protein synthesi Drug metabolism Lipid metabolis –1.0 Protein trafcking Energy production Cellular movement –5 0 5 –5 0 5 –5 0 5 Molecular transport Protein degradation Cellular compromise Antigen presentation Cellular developmen X-variate 1 X-variate 1 X-variate 1 Cell death and survival Amino acid metabolism Free radical scavengin Nucleic acid metabolism Vitamin & mineral metab.
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