Production of Homoplasmic Xenomitochondrial Mice

The unique features of mtDNA, together with the lack of a wide range of mouse cell mtDNA mutants, have hampered the creation of mtDNA mutant mice. To overcome these barriers mitochondrial defects were created by introducing mitochondria from different mouse species into Mus musculus domesticus (Mm)...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-02, Vol.101 (6), p.1685-1690
Main Authors: McKenzie, Matthew, Trounce, Ian A., Cassar, Carolyn A., Pinkert, Carl A., Seidel, George E.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological Sciences
Cell Line
Cell lines
Deoxyribonucleic acid
Disease models
DNA
DNA Primers
DNA, Mitochondrial - genetics
Feeder cells
Female
Fibroblasts
Genetics
Germ cells
L cells
Male
Mice
Mitochondrial DNA
Molecular Sequence Data
Mus dunni
Mus musculus domesticus
Mus spretus
Mutation
Polymerase chain reaction
Rodents
Transplantation, Heterologous
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Summary:The unique features of mtDNA, together with the lack of a wide range of mouse cell mtDNA mutants, have hampered the creation of mtDNA mutant mice. To overcome these barriers mitochondrial defects were created by introducing mitochondria from different mouse species into Mus musculus domesticus (Mm) mtDNA-less (ρ0) L cells. Introduction of the closely related Mus spretus (Ms) or the more divergent Mus dunni (Md) mitochondria resulted in xenocybrids exhibiting grossly normal respiratory function, but mild metabolic deficiencies, with 2- and 2.5-fold increases in lactate production compared with controls. The transfer of this model from in vitro to in vivo studies was achieved by introducing Ms and Md mitochondria into rhodamine-6G-treated Mm mouse embryonic stem (ES) cells. The resultant xenocybrid ES cells remained pluripotent, and live-born chimerae were produced from both Ms and Md xenocybrid ES cells. Founder chimeric females ( G0) were mated with successful germ-line transmission of Ms or Md mtDNA to homoplasmic G1offspring. These xenocybrid models represent the first viable transmitochondrial mice with homoplasmic replacement of endogenous mtDNA and confirm the feasibility of producing mitochondrial defects in mice by using a xenomitochondrial approach.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0303184101