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

Nature Medicine volume 7, pages934–940(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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Figure 1: Characterization of ΔmtDNA4696 in somatic cybrids.
Figure 2: Distribution of ΔmtDNA4696, a partially duplicated mtDNA and wild-type mtDNA in skeletal muscle, heart and kidney of mouse-0, -57 and -87, which respectively possessed 0%, 57% and 87% ΔmtDNA4696 in their tails.
Figure 3: Pathogenesis of ΔmtDNA4696 in skeletal muscles from mouse-0, -57 and -87.
Figure 4: Pathogenesis of ΔmtDNA4696 in hearts from mouse-0, -57 and -87.
Figure 5: Pathogenesis of ΔmtDNA4696 in kidneys from mouse-0, -57 and -87.
Figure 6: Effect of coexistence of similiar amounts of COX− and COX+ mitochondria within the same cells.

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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.

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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  1. Kazuto Nakada
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  2. Kimiko Inoue
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  8. Jun-Ichi Hayashi
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Correspondence to Jun-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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