| Project/Area Number |
06670760
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
MIYABAYASHI Shigeaki TOHOKU UNIVERSITY,SCHOOL OF MEDICINE,DEPARTMENT OF PEDIATRICS,ASSOCIATE PROFESSOR, 医学部, 教授 (20174203)
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| Co-Investigator(Kenkyū-buntansha) |
相川 純一郎 東北大学, 医学部附属病院, 講師 (30191844)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | mitochondrial disease / aging / MELAS / heteroplasmy / oxidative phospholyration / cybrid / mitochondrial DNA / mutation / ミトコンドリア病 / FACScan / 電子伝達系酸素 / ミトコンドリアDNA(mtDNA) / SV40 / cybrid |
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| Research Abstract |
Recently, heteroplasmy of wild type mitochondrial DNA (mtDNA) and mutant mtDNA with large-scale mtDNA deletions including several tRNA genes, with point mutations in mitochondrial tRNALue (UUR) gene at 3243 and 3271 and with a point mutation in mitochondrial tRNALys gene at nucleotide position 8344 and 8356 was shown to be closely associated with CPEO,MELAS,and MERRF,respectively. However, it seems to be uncertain that theses'relatives with low population of the mutation will be able to get out of onset of this disease for life.
Recently, hypotheses have been proposed that accumulation of various mtDNA somatic mutations during lifetime and the resultant decline of mitochondrial energy production properties play significant roles in the aging processes and in several degenerative diseases. We studied that mitochondrial biochemical function in fibroblasts from normal aged human subjects and from patients with verious mtDNA mutations. The age-related reduction of cytochrome c oxidase was revealed in fibroblasts from normal aged individuals. We also investigated the cybrid colons by fusing p0-HeLa cell and nuclear DNA-less fibroblasts with mtDNA mutations. The cybrid cells with 3243 or 3271 mutation showed quickly declined activity of COX at consisting more than 95% of this mutation, but the activity of complex I already decreased at lower population of these mutation. Fibroblasts from normal aged individuals, also the cybrid cells with mtDNA mutation showed a reduction of TCA cycle function using oxidation of pyruvate-2-[C^<14>]. High percentages of the mutation would be particularly sensitive to onset of the disease because of direct inhibition of oxidative phospholyration function, but lower percentages would be effective to expression thresholds associating with the age-related reduction of oxidative phospholyration.
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