Generation and application of mtDNA knockout mice as models for mitochondrial diseases

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Mice possessing pathogenic mutant mitochondrial DNA (mtDNA) would provide ideal systems for studying exactly how mutant mtDNAs are transmitted and distributed in tissues resulting in expression of mitochondrial diseases, but no effective procedures are available for their generation. Isolation of mtDNA-less (ρ^0) mouse cells enabled us to trap mouse mutant mtDNAs that had accumulated in somatic tissues into mtDNA repopulated ρ^0 cells (cybrids). We could isolate respiration-deficient cybrids with a deletion mutant mtDNA and introduce it into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice unexpectedly died as a consequence of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases. Escape ofJhe tissues with up to 90 % mutant mtDNA from expression of disease phenotypes was enabled by the extensive intermitochondrial interaction.