Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development
| Autor: | Yoshiaki Kikkawa, Akinori Shimizu, Shun Katada, Jun-Ichi Hayashi, Takayuki Mito, Hirotake Imanishi, Osamu Hashizume, Yukina Kato, Kazuto Nakada, Azusa Ota |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Aging
Mitochondrial Diseases Anatomy and Physiology Mouse Aging and Cancer lcsh:Medicine Mitochondrion medicine.disease_cause Biochemistry Hematologic Cancers and Related Disorders Mice B-cell lymphoma lcsh:Science Cells Cultured Energy-Producing Organelles Genetics Mutation Multidisciplinary Cancer Risk Factors Aging Premature Animal Models Hematology Phenotype Mitochondria Oncology Medicine Lymphomas Research Article Premature aging Mitochondrial DNA Lymphoma B-Cell Clinical Research Design Biology Bioenergetics DNA Mitochondrial Germline mutation Oxygen Consumption Model Organisms medicine Animals Kyphosis Animal Models of Disease Point mutation lcsh:R Alopecia Human Genetics medicine.disease Molecular biology lcsh:Q Physiological Processes |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 2, p e55789 (2013) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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