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Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes

Nature Genetics volume 26, pages 176–181 (2000)Cite this article

Abstract

Mice carrying mitochondrial DNA (mtDNA) with pathogenic mutations would provide a system in which to study how mutant mtDNAs are transmitted and distributed in tissues, resulting in expression of mitochondrial diseases. However, no effective procedures are available for the generation of these mice. Isolation of mouse cells without mtDNA (ρ0) enabled us to trap mutant mtDNA that had accumulated in somatic tissues into ρ0 cells repopulated with mtDNA (cybrids). We isolated respiration-deficient cybrids with mtDNA carrying a deletion and introduced this mtDNA into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice died because of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases.

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Figure 1: Genetic characterization of ΔmtDNA4696 in somatic cells.
Figure 2: Experimental scheme for producing heteroplasmic mice possessing wild-type mtDNA and exogenously introduced ΔmtDNA4696 from Cy4696 cybrids.
Figure 3: Transmission and distribution of ΔmtDNA4696 in F0–F3 mice.
Figure 4: Detection of a partially duplicated mtDNA and its distribution in tissues of F0–F3 generations.
Figure 5: Histochemical and morphological abnormalities observed in mice with predominant amounts of the mutant mtDNA.
Figure 6: Biochemical abnormalities of blood in mice with the mutant mtDNA.

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Author notes

  1. Kimiko Inoue and Kazuto Nakada: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biological Sciences, University of Tsukuba, Ibaraki, Japan

    Kimiko Inoue, Kazuto Nakada, Kotoyo Isobe & Jun-Ichi Hayashi

  2. Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki, Japan

    Jun-Ichi Hayashi

  3. Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan

    Kimiko Inoue & Atsuo Ogura

  4. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yu-ichi Goto

  5. Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    Kazuto Nakada & Ikuya Nonaka

Authors
  1. Kimiko Inoue
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Correspondence to Jun-Ichi Hayashi.

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Inoue, K., Nakada, K., Ogura, A. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat Genet 26, 176–181 (2000). https://doi.org/10.1038/82826

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