A model mouse for mitochondrial DNA-based diseases

Patient studies suggested that accumulation of pathogenic mitochondrial (mt) DNAs having large-scale deletion or point mutation and the resultant mitochondrial respiratory abnormalities are associated with a wide variety of disorders, such as mitochondrial diseases, neurodegenerative diseases, diabetes, and aging. Although the pathogenicities of these mtDNA mutations were proved by co-transmission of the mutant mtDNAs and respiration defects to human mtDNA-less cells, there is as yet no convincing reverse genetic evidence to explain whether accumulation of these pathogenic mutant mtDNAs in tissues is responsible for the expressions of various clinical phenotypes. In such situation, we have succeeded in generating mice with pathogenic deletion mutant mtDNA, named "mito-mice", by introduction of mitochondria with mtDNA which is deleted 4,696 bp (nt 7,759-12,454) including 6 tRNA genes and 7 structural genes (del-mtDNA). In the mito-mice, del-mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues, resulting in mitochondrial disease phenotypes, such as low body weight, lactic acidosis, ischemia, myopathy, hart block, deafness, male infertility, and renal failure. Thus, mito-mice are the first model animal for mtDNA-based diseases, and the mice should be valuable for screening effective drugs and testing therapies.