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Mitochondrial genetics

A clever way to model defects . . .

Nature Reviews Genetics volume 1, pages 84–85 (2000)Cite this article

The key to the authors' success was to isolate naturally occurring mtDNA mutations. This they did by fusing enucleated cells — prepared from mouse brain synaptosomes and carrying a mixed (heteroplasmic) population of mutated and wild-type mtDNA — with cells depleted of mtDNA, to make a cytoplasmic hybrid (cybrid) cell line. One cybrid clone was identified that carried a 4,696-base-pair mtDNA deletion, which removed six tRNA genes and seven structural genes. To generate mice with this deletion, the cybrid cells were enucleated, fused to pronuclear-stage embryos, and transplanted to female mice. Of 111 resulting newborn mice, 24 were heteroplasmic and, of these, five females — with varying loads of the deletion (5.7–13%) — transmitted the deletion to their offspring.

To investigate how closely the progeny of these mice modelled human mitochondrial disorders, the authors tested the mice for respiratory-chain function and for ragged red fibres (RRFs) in skeletal muscle, a feature caused by the accumulation of abnormal mitochondria. (The accompanying image shows muscle fibres from a person with a mtDNA deletion — the left asterix marks a RRF and the right one shows the loss of cytochrome c oxidase activity in the same fibre). Although the skeletal and cardiac muscles of mice with high loads of the deleted mtDNA were mosaic for respiratory chain function, as is often seen in human mitochondrial disorders, typical skeletal RRFs, as well as other features of human mtDNA disease, were not found. Mice with a high mtDNA load died after 200 days from kidney failure, a condition not normally associated with human mitochondrial disease.

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References

ORIGINAL RESEARCH PAPER

  1. Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nature Genet. 26, 176–181 (2000) [ Contents page]

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FURTHER READING

  1. Shoubridge, E. A. A debut for mito-mouse. Nature Genet. 26, 132–134 (2000) [ Contents page]

    Article  CAS  Google Scholar 

  2. Cottrell, D.A. et al. Role of mitochondrial DNA mutations in disease and aging. Ann. NY Acad. Sci. 908, 199–207 (2000)

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Authors
  1. Jane Alfred
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MITOMAP — A human mitochondrial genome database

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Alfred, J. A clever way to model defects . . .. Nat Rev Genet 1, 84–85 (2000). https://doi.org/10.1038/35038505

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