Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA (original) (raw)
- Article
- Published: August 2001
- Kimiko Inoue1,5 na1,
- Tomoko Ono1,
- Kotoyo Isobe1,
- Atsuo Ogura5,
- Yu-Ichi Goto4,
- Ikuya Nonaka3 &
- …
- Jun-Ichi Hayashi1,2
Nature Medicine volume 7, pages 934–940 (2001)Cite this article
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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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References
- Larsson, N.-G. & Clayton, D.A. Molecular genetic aspects of human mitochondrial disorders. Annu. Rev. Genet. 29, 151–178 (1995).
Article CAS Google Scholar - Wallace, D.C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).
Article CAS Google Scholar - Wang, J. et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21, 133–137 (1999).
Article CAS Google Scholar - Yamaoka, M. et al. Complete repopulation of mouse mitochondrial DNA-less cells with rat mitochondrial DNA restores mitochondrial translation but not mitochondrial respiratory functions. Genetics 155, 301–307 (2000).
CAS PubMed PubMed Central Google Scholar - Yamaoka, M., et al. Mice with only rat mtDNA are required as models of mitochondrial diseases. Biochem. Biophys. Res. Commun. 282, 707–711 (2001).
Article CAS Google Scholar - Inoue, K. et al. Isolation and characterization of mitochondrial DNA-less mouse cell lines and their application for trapping mouse synaptosomal mitochondrial DNA with deletion mutations. J. Biol. Chem. 272, 15510–15515 (1997).
Article CAS Google Scholar - Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse deletion mutant mtDNA into zygotes. Nature Genet. 26, 176–181 (2000).
Article CAS Google Scholar - Kaneda, H. et al. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc. Natl. Acad. Sci. USA 92, 4542–4546 (1995).
Article CAS Google Scholar - Shitara, H. et al. Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from liver cells, occurs throughout embryogenesis. Genetics 156, 1277–1284 (2000).
CAS PubMed PubMed Central Google Scholar - Yoneda, M., Miyatake, T. & Attardi, G. Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell with distinct organelles. Mol. Cell. Biol. 14, 2699–2712 (1994).
Article CAS Google Scholar - Lombes, A., Bonilla, E. & DiMauro, S. Mitochondrial encephalomyopathies. Rev. Neurol. 145, 671–689 (1989).
CAS PubMed Google Scholar - Muller-Hocker, J. Mitochondria and aging. Brain Pathol. 2, 149–158 (1992).
Article CAS Google Scholar - Szabolcs, M.J. et al. Mitochondrial DNA deletion: a cause of chronic tubulointerstitial nephropathy. Kidney Int. 45, 1388–1396 (1994).
Article CAS Google Scholar - Sciacco, M. et al. Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. 3, 13–19 (1994).
Article CAS Google Scholar - Hayashi, J.-I. et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA 88, 10614–10618 (1991).
Article CAS Google Scholar - Clayton, D.A. Transcription of the mammalian mitochondrial genome. Ann. Rev. Biochem. 53, 573–594 (1984).
Article CAS Google Scholar - Ono, T., Isobe, K., Nakada, K. & Hayashi, J.-I. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria, Nature Genet. 28, 272–275 (2001).
Article CAS Google Scholar - Hayashi, J.-I., Takemitsu, M., Goto, Y.-i. & Nonaka, I. Human mitochondria and mitochondrial genome function as a single dynamic cellular unit. J. Cell Biol. 125, 43–50 (1994).
Article CAS Google Scholar - Ito, S. et al. Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer's disease. Proc. Natl. Acad. Sci. USA 96, 2099–2103 (1999).
Article CAS Google Scholar - Seligman, A.M., Karnovsky, M.J., Wasserkrug, H.L. & Hanker, J.S. Nondroplet ultrastructural demonstration of cytochrome oxidase activity with a polymerizing osmophilic reagent, diaminobenzidine (DAB). J. Cell Biol. 38, 1–14 (1968).
Article CAS Google Scholar - Miyabayashi, S. et al. Cytochrome c oxidase deficiency in two siblings with Leigh encephalomyelopathy. Brain Dev. 6, 362–372 (1984).
Article CAS Google Scholar - Nonaka, I., Koga, Y., Ohtaki, E. & Yamamoto, M. Tissue specificity in cytochrome c oxidase deficient myopathy. J. Neurol. Sci. 92, 193–203 (1989).
Article CAS Google Scholar
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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- Kazuto Nakada and Kimiko Inoue: K.N. and K.I. contributed equally to this study.
Authors and Affiliations
- Institute of Biological Sciences, University of Tsukuba, Ibaraki, Japan
Kazuto Nakada, Kimiko Inoue, Tomoko Ono, Kotoyo Isobe & Jun-Ichi Hayashi - Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, Japan
Kazuto Nakada & Jun-Ichi Hayashi - Department of Ultrastructural Research, National Institte of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Kazuto Nakada & Ikuya Nonaka - Department of Mental Retardation and Birth Defect Research, National Institte of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Yu-Ichi Goto - Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
Kimiko Inoue & Atsuo Ogura
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- Kazuto Nakada
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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
- Received: 13 March 2001
- Accepted: 31 May 2001
- Issue Date: August 2001
- DOI: https://doi.org/10.1038/90976