Transmitochondrial Animals

To make a transmitochondrial animal, the ability to manipulate normal and mutant mitochondria in vivo has been a critical and difficult first step. In vivo mitochon-drial gene transfer remains a technological hurdle in the development of mitochondria-based genetic therapies and in the generation of experimental animal models for the study of mitochondrial dynamics and mitochondria-based traits. While gene transfer has been performed in a host of cell types and organisms, transfer of nuclear DNA has been the only demonstrable form of mammalian gene transfer, short of cell fusions, to date.

Rapid segregation of mtDNA genotypes could occur in mammals and was first demonstrated in Holstein cattle where pedigree records in the industry allowed detailed analysis of maternally related individual genotypes.[5] Segregation of mtDNA was investigated in maternal lineages of heteroplasmic mice created by cytoplast fusion[6'7] and by embryonic karyoplast transplantation.[8] Although mitochondrial segregation in somatic tissues is effective in some tissues and with increasing age, the preceding studies have shown that mtDNA heteroplasmy is maintained at stable levels throughout several generations. This would suggest that the mouse germline is not very effective in segregating mtDNA haplotypes. In cattle, however, highly heteroplasmic females will produce homoplasmic oocytes, whereas heteroplasmic bulls produce mostly heteroplasmic sperm, indicating that mtDNA segregation is very stringent in the female and practically absent in the male germline.[9] Together, these results suggest that mammalian species show variable patterns of mtDNA segregation.

In contrast to these techniques, our efforts to devise a direct mitochondria transfer technique offered certain advantages. Principally, the ability to use isolated mitochondria for the production of heteroplasmic mice would allow for investigations into the feasibility of genetic manipulation of mtDNA in vitro prior to mitochondria microinjection into zygotes.

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