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Updated: Aug 18, 2026
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
Mice with only rat mtDNA are required as models of mitochondrial diseases
1Institute of Biological Sciences, University of Tsukuba, Ibaraki, 305-8572, Japan.
Abstract:
We examined the possibility of generation of mice expressing mitochondrial dysfunction by introduction of exogenous mtDNA from different species using mouse mtDNA-less (rho(0)) cells as mtDNA recipients. For determination of how genetically distant species of mtDNA could replicate in cells with only the mouse nuclear genome, we introduced mtDNA of the Syrian hamster (Mesocricetus auratus) into mouse rho(0) cells, and found that its replication was not sufficient to propagate to following generations, probably due to significant incompatibility between mouse-nuclear and Syrian hamster-mitochondrial genomes. On the other hand, rat mtDNA, which propagated stably and expressed mitochondrial dysfunction in mouse cells, also disappeared rapidly by exogenous introduction of mouse mtDNA, suggesting that mouse mtDNA in mouse cells must be excluded completely before introduction of rat mtDNA for generation of mice with rat mtDNA as mitochondrial disease models.
Insights
Mitochondrial dysfunction models in mice require careful mtDNA selection. Introducing rat mtDNA into mouse cells shows promise for disease modeling, but complete mouse mtDNA exclusion is necessary for stable integration and propagation.
Area of Science:
- Mitochondrial genetics
- Comparative genomics
- Animal models for disease
Background:
- Mitochondrial DNA (mtDNA) plays a crucial role in cellular respiration.
- Generating animal models with specific mitochondrial defects is essential for studying mitochondrial diseases.
- Cross-species mtDNA compatibility with host nuclear genomes is a key factor in successful mitochondrial transplantation.
Purpose of the Study:
- To investigate the feasibility of creating mice with mitochondrial dysfunction by introducing exogenous mtDNA from different species into mouse mtDNA-less (rho(0)) cells.
- To assess the replicative capacity and compatibility of heterologous mtDNA within the mouse nuclear environment.
- To establish a protocol for generating mouse models of mitochondrial disease using specific heterologous mtDNA.
Main Methods:
- Utilizing mouse rho(0) cells as recipients for exogenous mtDNA.
- Introducing Syrian hamster (Mesocricetus auratus) mtDNA into mouse rho(0) cells to assess interspecies compatibility.
- Introducing rat mtDNA into mouse rho(0) cells to evaluate its propagation and potential for inducing mitochondrial dysfunction.
- Investigating the competitive exclusion dynamics between endogenous mouse mtDNA and introduced rat mtDNA.
Main Results:
- Syrian hamster mtDNA failed to propagate in mouse rho(0) cells, indicating significant nuclear-mitochondrial genomic incompatibility.
- Rat mtDNA stably propagated in mouse cells and induced mitochondrial dysfunction.
- Introduced rat mtDNA was rapidly eliminated upon co-introduction with mouse mtDNA, highlighting the need for complete mouse mtDNA clearance.
- Successful generation of mouse models with rat mtDNA requires prior complete exclusion of endogenous mouse mtDNA.
Conclusions:
- Cross-species mtDNA transplantation is feasible but highly dependent on the genetic distance between donor mtDNA and host nuclear genome.
- Rat mtDNA is a suitable candidate for generating mouse models of mitochondrial dysfunction due to its compatibility with the mouse nuclear genome.
- A critical prerequisite for establishing mouse models with specific heterologous mtDNA is the complete elimination of endogenous mouse mtDNA to prevent competitive exclusion.
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