Mitochondrial DNA Mutations in Mutator Mice Confer Respiration Defects and B-Cell Lymphoma Development

Takayuki Mito,Azusa Ota,Kazuto Nakada,Hirotake Imanishi,Jun-Ichi Hayashi,Yukina Kato,Yoshiaki Kikkawa,Shun Katada,Akinori Shimizu,Osamu Hashizume,Yidong Bai

doi:10.1371/journal.pone.0055789

Takayuki Mito, Azusa Ota + Show 9 more

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https://doi.org/10.1371/journal.pone.0055789

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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 (ρ0) 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.

Highlights

It has been hypothesized that pathogenic Mitochondrial DNA (mtDNA) mutations that induce significant mitochondrial respiration defects cause mitochondrial diseases [1,2] and could be involved in aging and age-associated disorders including tumor development [1,2,3,4,5]
Immortalized 3T3 cell lines obtained from m/m mutator mice (3T3m/m) and mito-miceD (3T3D) showed a similar reduction in both c oxidase (COX) activity (Fig. 1A) and O2 consumption rates compared to controls (Fig. 1B)
By generating mtDNA mutator mice with the same B6J nuclear background as that of mito-miceD, we can provide an answer to the question of why premature aging phenotypes are exclusively observed in homozygous m/m mutator mice but not in transmitochondrial mito- miceD, even though they both express significant respiration defects

Summary

Introduction

It has been hypothesized that pathogenic mtDNA mutations that induce significant mitochondrial respiration defects cause mitochondrial diseases [1,2] and could be involved in aging and age-associated disorders including tumor development [1,2,3,4,5]. Our previous studies [9,10] showed that transmitochondrial mito-miceD carrying mtDNA with a largescale deletion mutation (DmtDNA) expressed age-associated respiration defects, but not express the premature aging phenotypes. It appears to be discrepant that premature aging phenotypes are exclusively observed in mtDNA mutator mice [6,7,8], but not in transmitochondrial mito-mice [9,10,11,14], even though they all express mitochondrial respiration defects caused by mutated mtDNA

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