@article{38d24159f9a54d3ab13e000997c18a66,
title = "Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice",
abstract = "Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e., the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of an AKR/J mouse strain (B6-mtAKR) in a C57BL/6 J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to that of wild-type C57BL/6 J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair the metabolic health and lifespan in mice.",
author = "Misa Hirose and Paul Schilf and Yask Gupta and Kim Zarse and Axel K{\"u}nstner and Anke F{\"a}hnrich and Hauke Busch and Junping Yin and Wright, {Marvin N.} and Andreas Ziegler and Marie Vallier and Meriem Belheouane and Baines, {John F.} and Diethard Tautz and Kornelia Johann and Rebecca Oelkrug and Jens Mittag and Hendrik Lehnert and Alaa Othman and Olaf J{\"o}hren and Markus Schwaninger and Cornelia Prehn and Jerzy Adamski and Kensuke Shima and Jan Rupp and Robert H{\"a}sler and Georg Fuellen and R{\"u}diger K{\"o}hling and Michael Ristow and Ibrahim, {Saleh M.}",
note = "Funding Information: The authors thank Miriam Daumann, Miriam Freitag, Beate Laube, Doris P{\"o}hlmann, Melanie Vollstedt, and Nicole Thomsen for excellent technical assistance. We thank Stephanie Derer and Christian Sina for valuable discussion. This work was supported by grants from the Bundesministerium f{\"u}r Bildung und Forschung (BMBF, 0315892B), DFG (EXC 306 and CRC 1182), University of L{\"u}beck (P01-2012), the Swiss National Science Foundation (Schweizerischer Nationalfonds, SNF 31003A_156031), and the European Union{\textquoteright}s Horizon 2020 research and innovation program (633589). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-24290-6",
language = "British English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}