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

Nature Medicine volume 7, pages 934–940 (2001)Cite this article

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.).

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Author notes

  1. Kazuto Nakada and Kimiko Inoue: K.N. and K.I. contributed equally to this study.

Authors and 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

Authors

  1. Kazuto Nakada
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  2. Kimiko Inoue
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  3. Tomoko Ono
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  4. Kotoyo Isobe
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  5. Atsuo Ogura
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  6. Yu-Ichi Goto
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  7. Ikuya Nonaka
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  8. Jun-Ichi Hayashi
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Corresponding author

Correspondence toJun-Ichi Hayashi.

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Nakada, K., Inoue, K., Ono, T. et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.Nat Med 7, 934–940 (2001). https://doi.org/10.1038/90976

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