Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development

• Published in: PloS one 2013-02, Vol.8 (2), p.e55789-e55789
• Main Authors: Mito, Takayuki, Kikkawa, Yoshiaki, Shimizu, Akinori, Hashizume, Osamu, Katada, Shun, Imanishi, Hirotake, Ota, Azusa, Kato, Yukina, Nakada, Kazuto, Hayashi, Jun-Ichi
• Format: Article
• Language: English
• Subjects: Abnormalities; Age; Aging; Aging - genetics; Aging - metabolism; Aging, Premature - genetics; Aging, Premature - metabolism; Alopecia; Alopecia - genetics; Alopecia - metabolism; Animals; B-cell lymphoma; Biology; Cancer; Cancer genetics; Cells, Cultured; Clonal deletion; Coding; Defects; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Electron transport; Environmental science; Fibroblasts; Gene deletion; Gene mutation; Genes; Genetic aspects; House mouse; Kyphosis; Kyphosis - genetics; Kyphosis - metabolism; Life span; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphomas; Medicine; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial DNA; Mutation; Oxygen Consumption; Phenotype; Polymerase; Proofreading; Respiration; Rodents; Stem cells; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055789

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.