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Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA

Nature Medicine 7, 934–940 (2001) | Download Citation

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Abstract

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (ΔmtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with ΔmtDNA4696 showed normal COX activity until ΔmtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with ΔmtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.

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Acknowledgements

This work was supported by a grant for a Research Fellowship from the Japan Society for Promotion of Science for Young Scientists (to K.N., K.I. and K.I.); by a grant for the Hayashi project of TARA, University of Tsukuba; by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to J.-I.H.); and by Health Sciences Research Grants for Research on Brain Science from the Ministry of Health and Welfare of Japan (to J.-I.H, I.N. and Y.-i.G.).

Author information

    • Kazuto Nakada
    •  & Kimiko Inoue

    K.N. and K.I. contributed equally to this study.

Affiliations

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

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

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

    • Kazuto Nakada
    •  & Jun-Ichi Hayashi

  3. Department of Ultrastructural Research, National Institte of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    • Kazuto Nakada
    •  & Ikuya Nonaka

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

    • Yu-Ichi Goto

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

    • Kimiko Inoue
    •  & Atsuo Ogura

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Correspondence to Jun-Ichi Hayashi.

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DOI

https://doi.org/10.1038/90976