2001 Fiscal Year Final Research Report Summary
Generation and application of mtDNA knockout mice as models for mitochondrial diseases
| Project/Area Number |
10358018
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Laboratory animal science
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| Research Institution | University of Tsukuba |
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Principal Investigator |
HAYASHI Jun-ichi University of Tsukuba, Institute of Biological Sciences, Professor, 生物科学系, 教授 (60142113)
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| Co-Investigator(Kenkyū-buntansha) |
GOTO Yu-ichi National Center of Neurology and Psychiatry, National Institute of Neuroscience, Department of Mental Retardation and Birth Defect Research, 神経研究所, 部長 (20225668)
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| Project Period (FY) |
1998 – 2001
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| Keywords | Mouse mtDNA / mtDNA Mutation / Mitochondrial transfer / Disease model mice / mitochondrial tRNA |
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| Research Abstract |
Mice possessing pathogenic mutant mitochondrial DNA (mtDNA) would provide ideal systems for studying exactly how mutant mtDNAs are transmitted and distributed in tissues resulting in expression of mitochondrial diseases, but no effective procedures are available for their generation. Isolation of mtDNA-less (ρ^0) mouse cells enabled us to trap mouse mutant mtDNAs that had accumulated in somatic tissues into mtDNA repopulated ρ^0 cells (cybrids). We could isolate respiration-deficient cybrids with a deletion mutant mtDNA and introduce it into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice unexpectedly died as a consequence of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases. Escape ofJhe tissues with up to 90 % mutant mtDNA from expression of disease phenotypes was enabled by the extensive intermitochondrial interaction.
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