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Selection of rodent species appropriate for mtDNA transfer to generate transmitochondrial mito-mice expressing
Shunkei Enoki1, Akinori Shimizu, Chisato Hayashi
1Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8572, Japan.
Abstract:
Previous reports have shown that transmitochondrial mito-mice with nuclear DNA from Mus musculus and mtDNA from M. spretus do not express respiration defects, whereas those with mtDNA from Rattus norvegicus cannot be generated from ES cybrids with mtDNA from R. norvegicus due to inducing significant respiration defects and resultant losing multipotency. Here, we isolated transmitochondrial cybrids with mtDNA from various rodent species classified between M. spretus and R. norvegicus, and compared the O2 consumption rates. The results showed a strong negative correlation between phylogenetic distance and reduction of O2 consumption rates, which would be due to the coevolution of nuclear and mitochondrial genomes and the resultant incompatibility between the nuclear genome from M. musculus and the mitochondrial genome from the other rodent species. These observations suggested that M. caroli was an appropriate mtDNA donor to generate transmitochondrial mito-mice with nuclear DNA from M. musculus. Then, we generated ES cybrids with M. caroli mtDNA, and found that these ES cybrids expressed respiration defects without losing multipotency and can be used to generate transmitochondrial mito-mice expressing mitochondrial disorders.
Insights
Mitochondrial genome compatibility is key for creating mito-mice. Researchers found that using mitochondrial DNA (mtDNA) from Mus caroli in mice with nuclear DNA from Mus musculus avoids respiration defects, enabling the creation of disease models.
Area of Science:
- Mitochondrial genetics
- Comparative genomics
- Developmental biology
Background:
- Transmitochondrial mito-mice are models for studying mitochondrial disorders.
- Interspecies mitochondrial DNA (mtDNA) transfer can lead to incompatibility with nuclear genomes, causing respiration defects and loss of multipotency.
- Previous studies showed varying outcomes with different rodent mtDNA donors.
Purpose of the Study:
- To investigate the compatibility of mtDNA from various rodent species with Mus musculus nuclear DNA.
- To identify an appropriate mtDNA donor for generating transmitochondrial mito-mice with mitochondrial disorders.
- To assess the impact of phylogenetic distance on nuclear-mitochondrial genome compatibility.
Main Methods:
- Isolation of transmitochondrial cybrids with mtDNA from diverse rodent species.
- Comparison of oxygen consumption rates in cybrids.
- Generation of ES cybrids with Mus caroli mtDNA.
- Assessment of multipotency and respiration defects in ES cybrids.
Main Results:
- A negative correlation was observed between phylogenetic distance and oxygen consumption rates.
- Mitochondrial genome incompatibility increases with phylogenetic distance from Mus musculus.
- Mus caroli mtDNA was identified as compatible with Mus musculus nuclear DNA.
- ES cybrids with Mus caroli mtDNA exhibited respiration defects without losing multipotency.
Conclusions:
- Coevolution of nuclear and mitochondrial genomes dictates compatibility.
- Mus caroli is a suitable mtDNA donor for creating transmitochondrial mito-mice models of mitochondrial disorders.
- These mito-mice can be used to study mitochondrial diseases without compromising developmental potential.
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