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Studies on Pathogenesis of Mitochondrial Diseases

Research Project

Project/Area Number 02304043
Research Category

Grant-in-Aid for Co-operative Research (A)

Allocation TypeSingle-year Grants
Research Field Pediatrics
Research InstitutionTOHOKU UNIVERSITY

Principal Investigator

TADA Keiya  TOHOKU UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF PEDIATRICS, PROFESSOR, 医学部, 教授 (20046907)

Co-Investigator(Kenkyū-buntansha) MIYABAHASHI Shigeaki  TOHOKU UNIVERSITY,SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (20174203)
宝来 聰  国立遺伝学研究所, 助教授 (40126157)
WADA Yoshiroh  NAGOYA CITY UNIVERSITY MEDICAL SCHOOL,DEPARTMENT OF PEDIATRICS,PROFESSOR, 医学部, 教授 (30004849)
OZAWA Takayuki  NAGOYA UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF BIOCHEMISTRY, PROFESSOR, 医学部, 教授 (80022771)
KAGAWA Yasuo  JICHI MEDICAL SCHOOL, DEPARTMENT OF BIOCHEMISTRY, PROFESSOR, 教授 (30048962)
Project Period (FY) 1990 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 1992: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1991: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1990: ¥5,700,000 (Direct Cost: ¥5,700,000)
Keywordsmitochondrial encephalomyopathy / mitochondrial DNA / MELAS / heteroplasmy / oxidative phosphorylation / fibroblasts / SV40 cell line / p0 cells / ミトコンドリアDNA欠失 / ミトコンドリア点変異 / CPEO / 遺伝子ファミリ- / 相補作用 / 一塩基置換
Research Abstract

We investigated the distribution and expression of 3243 mutation,the most common genetic defect, in the skeletal muscle of 18 patients with MELAS. This mtDNA mutation was present in 12 of 18 patients(67%). The proportion of this mutation in muscle ranged from 50 to 80% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives on family study. Furthermore the proportion of 3243 mutation in skeletal muscle had good relation to an age of suffering first stroke like attack.
In the enzymatic study,complex I-III activity was markedly decreased in the skeletal muscle mitochondria of all the patients with this mutation. The decrease of complex I had also clear relation to the population of this mtDNA mutation. It is reason that complex I is more components of peptides encoding from mtDNA than complex IV(COX), and mtDNA mutation is more harmful to its assembly.This fact is likely to accord a common decrease of complex I activity in muscle mitochondria from MELAS patients.
We investigated the cybrid colons by fusing p0-HeLa cell and nuclear DNA- less fibroblasts with 3243 mutation showed quickly declined activity of COX at consisting more than 95% of this mutation. However the activity of complex I already decreased at lower population of this mutation instead of the normal activity of COX.
Our data seems to indicate that 3243 mutation directly affects the inhibit of oxidative phospholyration and its quantity is a main factor to onset of MELAS with this mutation.

Report

(4 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] S.Miyabayasi,et.al.: "A new type of mitochondrial DNA deletion in patients with encephalomyopathy" J.Inherit.Metab.Dis.14. 805-812 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K.Haginoya,et.al.: "Cytochrome C oxidase-deficient mitochondria in mitochondrial myopathy" Padiatr.Neurol.8. 13-18 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Miyabayashi,et.al.: "Defects of mitochondrial respiratory enzymes in cloned cells from MELAS fibroblasts" J.Inherit.Metab.15. 797-802 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Miyabayashi,et.al.: "Clinical and biochemical phenotype of MELAS mutation" J.Inherit.Metab.Dis.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Miyabayashi,et.al.: "New type of mitochondrial DNA deletion found in Leign's encephalomyelopathy"

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Miyabayashi,et.al.: "Familial MELAS (mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes) with cytochrome b deficiency"

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyabayashi,S., Hanamizu, H., Endo, H., Tada, K. & Horai, S.: "A new type of mitochondrial DNA deletion in patients with encephalomyopathy." J.Inherit.Metab.Dis.14(5). 805-812 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Haginoya, K., Miyabayashi, S., Iinuma, K., Okino, E., Maesaka, H. & Tada, K.: "Cytochrome C oxidase-deficient mitochondria in mitochondrial myopathy." Pediatr.Neurol.8(1). 13-18 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyabayashi, S., Hanamizu, H., Nakamura, R., Endo, H. & Tada, K.: "Defects of mitochondrial respiratory enzymes in cloned cells from MELAS fibroblasts." J.Inherit.Metab.Dis.15(5). 797-802 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyabayashi, S., Hanamizu, H., Nakamura, R., & Tada, K.: "Clinical and biochemical phenotype of MELAS mutation." J.Inherit.Metab.Dis.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyabayashi, S., Hanamizu, H., Endo, H., Tada, K. & Horai, S.: "New type of mitochondrial DNA deletion found in Leigh's encephalomyelopathy."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyabayashi, S., Endo, H., Haginoya, K., Su, C.C., Watanabe, T., Irimada, K., Tsuchida, S. & Tada, K.: "Familial MELAS(mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes)with cytochrome b deficiency."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K.Haglnoya, et.al.: "Cyrochrome C oxidase-deficient mitochondria in mitochondrial myopathy" Pediatr.Neurol.8. 13-18 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Miyabayashi,et al.: "Defects of mitochondrial respiratory enzymes in cloned cells from MELAS fibroblasts" J. Ingerit. Metab.15. 797-802 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Miyabayashi,et.al.: "Clinical and biochemical phenotype of MELAS mutation" J. Ingerit. MetaB. Dis.(in press).

    • Related Report
      1992 Annual Research Report
  • [Publications] Miyabayashi,S.et al.: "Mitochondrial DNA deletion in patients with myopathy." Mitochondrial Encephalomyopathy. 7. 153-159 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Miyabayashi,S.et al.: "A new type of mitochondrial DNA deletion in patients with encephalomyopathy." J.Inherit.Meteb.Dis.14. 805-812 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hayashi,J.I.et al.: "Introduction of diseaseーrelated mitochondrial DNA deletions into Hela cells lacking mitochondrial DNA results in mitochondrial dysfunction." Proc.Nati.Acad.Sci.USA. 88. 10614-10618 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Goto,Y.et al.: "A new mtDNA mutation associated with mitochondrial myopathy,encephalopathy,lactic acidosis and strokeーlike episodes(MELAS)." Biochim.Biophys.Acta. 1097. 238-240 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ozawa,T.et al.: "Patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson's disease and mitochondrial encephalomyopathy." Biochem.Biophys.Res.Commun.177. 518-525 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ozawa,T.et al.: "Distinet clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson's disease." Biochem.Biophys.Res.Commun.176. 938-946 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Y.Goto;S.Horai,et al.: "A mutation in the tRNA^<Leu(UUR)> gene associated with the MELAS subgroup of mitochondrial encephalomyopathies" Nature. 348. 651-653 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] S.Miyabayashi;K.Tada,et a.: "A new type of mitochondrial DNA deletion in patients with encephalomyopathy" J.Inherit.Metab.Dis.

    • Related Report
      1990 Annual Research Report
  • [Publications] S.Miyabayashi;K.Tada,et al.: "Familial MELAS (mitochondrial myopathy,encephalopathy,lactic acidosis,and strokeーlike episodes) with cytochrome b deficiency"

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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