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.