TY - JOUR
T1 - Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice
AU - Hirose, Misa
AU - Schilf, Paul
AU - Gupta, Yask
AU - Zarse, Kim
AU - Künstner, Axel
AU - Fähnrich, Anke
AU - Busch, Hauke
AU - Yin, Junping
AU - Wright, Marvin N.
AU - Ziegler, Andreas
AU - Vallier, Marie
AU - Belheouane, Meriem
AU - Baines, John F.
AU - Tautz, Diethard
AU - Johann, Kornelia
AU - Oelkrug, Rebecca
AU - Mittag, Jens
AU - Lehnert, Hendrik
AU - Othman, Alaa
AU - Jöhren, Olaf
AU - Schwaninger, Markus
AU - Prehn, Cornelia
AU - Adamski, Jerzy
AU - Shima, Kensuke
AU - Rupp, Jan
AU - Häsler, Robert
AU - Fuellen, Georg
AU - Köhling, Rüdiger
AU - Ristow, Michael
AU - Ibrahim, Saleh M.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045422574&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-24290-6
DO - 10.1038/s41598-018-24290-6
M3 - Journal articles
C2 - 29651131
AN - SCOPUS:85045422574
SN - 2045-2322
VL - 8
SP - 5872
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 8:5872
ER -
