title: Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.
abstract: Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0)) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.
authors: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors: Takayuki
authors: T
authors: Mito
authors: Yoshiaki
authors: Y
authors: Kikkawa
authors: Akinori
authors: A
authors: Shimizu
authors: Osamu
authors: O
authors: Hashizume
authors: Shun
authors: S
authors: Katada
authors: Hirotake
authors: H
authors: Imanishi
authors: Azusa
authors: A
authors: Ota
authors: Yukina
authors: Y
authors: Kato
authors: Kazuto
authors: K
authors: Nakada
authors: Jun-Ichi
authors: J
authors: Hayashi
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000505:Alopecia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D007738:Kyphosis / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial