Studies on pathogenesis and gene therapy using mice with the mutated mtDNA in tRNA genes

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(1) Sato, A. et al. Proc. Natl. Acad. Sci. USA 102: 16765-16770. 2005Pathogenic mutations in mtDNAs have been shown to be responsible for expression of respiration defects and resultant expression of mitochondrial diseases. This study directly addressed the issue of gene therapy of mitochondrial diseases using nuclear transplantation of zygotes of trans-mitochondria mice (mito-mice). Mito-mice expressed respiration defects and mitochondrial diseases due to accumulation of mtDNA carrying a large-scale deletion (ΔmtDNA). Second polar bodies were used as biopsy samples for diagnosis of mtDNA genotypes of mito-mouse zygotes. Nuclear transplantation was carried out from mito-mouse zygotes to enucleated normal zygotes, and was shown to rescue all the F_0 progenies from expression of respiration defects throughout their lives. This -procedure should be applicable to patients with mitochondrial diseases for preventing their children from the diseases.(2) Sato, A. et al. Proc. Natl. Acad. Sci. … More USA 102: 6057-6062. 2005The problem of whether recombinant mtDNAs are created in mammalian cells has been controversial for many years. We show convincing evidence for the very rare creation of recombinant mtDNA haplotypes by isolating human somatic hybrid cells and by generating mice carrying two different mtDNA haplotypes. Such an extremely low frequency of mtDNA recombination does not require any revision of important concepts on human evolution that are based on its absence.(3) Liqin, C., et al. Nature Genet. 39:386-390, 2007The observations of rapid shifts in mtDNA variants between generations have originated the bottleneck theory. A prevalent hypothesis which has long been proposed is that a massive reduction in mtDNA content during early oogenesis leads to the bottleneck. To test this we estimated the mtDNA copy single exhibited consistent and moderate mtDNA copy numbers across developmental stages, while primary oocytes demonstrated substantial mtDNA expansion during early oocyte maturation. Some somatic cells possess a very low mtDNA copy number. We also demonstrated that PGCs have more than 100 mitochondria per cell. Taken together, we conclude that the mitochondrial bottleneck is not generated due to a mtDNA copy number drastic decline in early oogenesis rather to a small effective number of segregation units for mtDNA in mouse germ cells. Some somatic cell lineages have a narrow bottleneck during early differentiation. These results provide new information for generating mtDNA segregation models and for understanding of recurrence risks for mtDNA diseases. Less