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Construction of transgenic mice into which mutant mitochondrial DNA is artificially introduced.

Research Project

Project/Area Number 04557012
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionInstute of Gerontology, Nippon Mrdical School (1994)
Jichi Medical University (1992-1993)

Principal Investigator

OHTA Shigeo  Division of Biochemistry, Institute of Gerontology, Nippon Medical School, Professor, 老人病研究所, 教授 (00125832)

Co-Investigator(Kenkyū-buntansha) HAYASHI Jun-icji  Institute of Biological Sciences, University of Tsukuba, Associate Professor, 生物科学系, 助教授 (60142113)
香川 靖雄  自治医科大学, 医学部, 教授 (30048962)
猪原 直弘  自治医科大学, 医学部, 助手 (60232576)
遠藤 仁司  自治医科大学, 医学部, 助手 (50221817)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥18,500,000 (Direct Cost: ¥18,500,000)
Fiscal Year 1994: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1993: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1992: ¥12,700,000 (Direct Cost: ¥12,700,000)
KeywordsMitochondria / Transgenic mouse / Cybrid / Respiratory chain / particle gun / Cell fusion / Mitochondrial encephalomyopathy / Cardiomyopathy / タンパク質合成 / Alpers病 / 老化 / パーラィクルガン / ミトコンドリアDNA / ミトコンドリア胸筋症 / 遺伝子病 / 遺伝子導入 / 金属粒子 / 遺伝子銃
Research Abstract

mtDNA with a point mutation in the tRNA^<Ile> gene at nucleotide position 4269 found in a patient with fatal cardiomyopathy and mtDNA with a point mutation in the tRNA^<Arg> gene at 10410 found in a patient with Alpers disease were transferred cytoplasmically to rho゚ HeLa cells (HeLa cells lacking mtDNA) to determine whether these novel mtDNA mutations in the tRNA genes are responsible for the defects in mitochondrial respiration function observed in these diseases. Cybrid clones (clones of rho゚ HeLa cells with mtDNA from the patients) were isolated, and respiratory function and morphology of the mitochondria of the cybrid clones containing wild-type mtDNA and mutant mtDNA predominantly were compared. The results showed that accumulation of mutant mtDNA at 4269 alone without defects in the nuclear genome was sufficient to produce a disease phenotype, while mutant mtDNA at 10410 was not related to pathogenesis and reflected one of the rare polymorphic sites of human mtDNA.Moreover, we found that mitochondria in living cells were significantly swollen only when they contained predominantly the pathogenic mutant mtDNA,suggesting that the functional abnormalitiy of mitochondria induced by pathogenic mtDNA mutations in tRNA genes is always associated with their swollen structure.

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] 太田成男 他: "Gene structure of human mitochondrial ATP synthase g-subunit ; Tissue specificity produced by RNA splicing." J.Biol.Chem.268. 24950-24958 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 太田成男 他: "Accumulation of mtDNA with a mutation at position 3271 in tRNA-Leu (UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function." Biochem.Biophys.Res.Commun.197. 1049-1055 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 太田成男 他: "Content of mutant mitochondrial DNA and organ-dysfunction in a patient with a MELAS-subgroup of mitochondrial encephalomyopathies." J.Neurol.Sci.120. 174-179 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 太田成男 他: "Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction." J.Biol.Chem.269. 6878-6883 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 太田成男 他: "Widespread tissue distribution of multiple mitochondrial DNA deletions in familial mitochondrial myopathy" Muscle and Nerve. 17. 741-746 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 太田成男 他: "Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA with pathogenic point mutations in tRNA genes." J.Biol.Chem.269. 19060-19066 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Matsuda, C., Endo, H., Ohta, S.and Kagawa, Y.: "Gene structure of human mitochondrial ATP synthase g-subunit ; Tissue specificity produced by RNA splicing.categorization of patients in Long-Ter" J.Biol.Chem.268. 24950-24958 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, J-I., Ohta, S.Takai, D., Miyabayashi, S., Sakuta, R., Goto, Y-i., and Nonaka, I.: "Accumulation of mtDNA with a mutation at position 3271 in tRNA-Leu (UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function." Biochem.Biophys.Res.Commun.197 (3). 1049-1055 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Shiraiwa, N., Ishii, A., Iwamoto, H., Mizusawa, H., Kagawa, Y., and Ohta, S.: "Content of mutant mitochondrial DNA and organ-dysfunction in a patient with a MELAS-subgroup of mitochondrial encephalomyopathies." J.Neurol.Sci.120. 174-179 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, J-I., Ohta, S., Kagawa, Y., Kondo, H., Kaneda, H., Yonekawa, H., Takai, D., and Miyabayashi, S.: "Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction." J.Biol.Chem.269 (9). 6878-6883 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kawashima, S., Ohta, S., Kagawa, Y., Yoshida, M., Nishizawa, M.: "Widespread tissue distribution of multiple mitochondrial DNA deletions in familial mitochondrial myopathy" Muscle and Nerve. 17. 741-746 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, J-I., Ohta, S., Kagawa, Y., Takai, D., Miyabayashi, S., Tada, K., Nonaka, I.: "Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA with pathogenic point mutations in tRNA genes." J.Biol.Chem.269, (29). 19060-19066 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] J-I.Hayashi,S.Ohta, 他: "Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction." J.Biol.Chem.269. 6878-6883 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] T.Koike,S.Ohta 他: "Transcription of the MRP RNA gene in frog stage I oocytes requires a novel cis-element.Novel Biochem." Biphys.Res.Comun.202. 225-233 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.Akiyama,S.Ohta, 他: "Gene structure and cell type-specific expression of the human ATP synthase α subunit." Biochim.Biophys.Acta. 1219. 129-140 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.Kawashima,S.Ohta, 他: "Widespread tissue distribution of multiple mitochondrial DNA deletions in familial mitochondrial myopathy." Muscle and Nerve. 17. 741-746 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] J-I.Hayashi,S.Ohta, 他: "Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA With pathogenic point mutations in tRNA genes." J.Biol.Chem.269. 19060-19066 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] K.Nakano,S.Ohta, 他: "Isolation,characterization and structural organization of the gene and pseudogene for the dihydrolipoamide succinyltransferase component of the human 2-oxoglutarate dehydrogenase complex." Eur.J.Biochem.224. 179-189 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hayashi,J-I.,他: "Accumulation of mtDNA with a mutaion at position 3271 in tRNA-Leu(UUR)gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function" Biochem Biophys.Res.Commun.197. 1049-1055 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Shiraiwa,N.,他: "Content of mutant mitochndrial DNA and organ-dysfunction in a patient with a MELAS-subgroup of mitochondrial encephalomyopathies." J.Neurol.Sci.120. 174-179 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nakano,K.,他: "Human dihydrolipoamide succinyltransferase;cDAN cloning and localization on chromosome 14q24.2-q24.3" Biochim Biophys.Acta.1216. 360-368 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Matsuda,C.,他: "Gene structure of human mitachondrial ATP synthase gamma-subunit;Tissue specificity produced by RNA splicing." J.Biol Chem..268. 24950-24958 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tominaga,K.,他: "Smaller isoform of human mitochondrial transcription factor 1:Its wide distribution and producition by alternative splicing." Biochem Biophys.Res.Commun. 194. 544-551 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Takiyama,Y.,他: "The gene for Machado-Joseph disease mapa to human chromosome 14〓" Nature Genetics. 4. 300-304 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 太田 成男: "変異ミトコンドリアtRNAによるミトコンドリア病の発症機序" Cell Science. 8. 714-721 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 太田 成男: "ミトコンドリアDNAの遺伝情報の発現制御" 神経研究の進歩. 36. 986-992 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 太田 成男: "ミトコンドリア遺伝子と核遺伝子の関係" 代謝. 29. 209-216 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 太田 成男: "ミトコンドリア遺伝子点突然変異による疾患" 細胞工学. 11. 47-53 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kabayashi,Y.: "The mutant mitochondrial genes in mitochondrial myopathy,encepholopathy,lactic acidosis and stroke-like episodes (MELAS)were selectively amplified through generations." J.Inher.Metab.Dis.15. 803-808 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tominaga,K.: "Upstream region of a genomic gene for human mitochondrial transcription factor 1" Biochim.Biophys.Acta. 1131. 217-219 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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