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1994 Fiscal Year Final Research Report Summary

Involvement of mitochondrial DNA mutations in aging and mitochondrial diseases

Research Project

Project/Area Number 04404029
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionNagoya University

Principal Investigator

OZAWA Takayuki  Faculty of Medicine, Univ of Nagoya, Professor, 医学部, 教授 (80022771)

Co-Investigator(Kenkyū-buntansha) HAYAKAWA Mika  Faculty of Medicine, Univ of Nagoya Assistant Professor, 医学部, 助手 (10238090)
TANAKA Masashi  Faculty of Medicine, Univ of Nagoya Associate professor, 医学部, 助教授 (60155166)
Project Period (FY) 1992 – 1994
Keywordsmitochondrial DNA / 8-hydroxydeoxyguanosine / aging / point mutations / oxidative stress / cardiomyopathy / deleted mtDNA / reactive oxygen species
Research Abstract

To elucidate the contribution of mitochondrial abnormality both to the pathogenesis of mitochondrial disease and to the degenerative changes associated with aging, we developed a rapid method for analyzing the entire sequence of the mitochondrial genome. The analysis revealed both mit^- mutations, which alter amino acids that are highly conserved among species, and syn^- mutations, which alter phylogenetically conserved nucleotides in tRNA and rRNA genes. The life spans of patients who possessed both mit^- and syn^-mutations were significantly shorter than those of patients with only either mit^- or syn^- mutations (Lancet 345 : 189,1995). The analysis of the four-fold degeneration sites in the coding regions revealed that the nucleotide substitutions occur asymmetrically with respect to the strands (Genomics 22 : 327-335,1994). We also demonstrated that age-dependent exponential accumulation of deleted mtDNA and 8-hydroxydeoxyguanosine. The PCR detection system with 180 primer pairs revealed that a patient with mitochondrial cardiomyopathy who died at 19 years old possessed numerous deleted mtDNAs in the amounts comparable to those in aged individuals (BBRC202 : 102-110,1995). Teses results suggest that the combination of maternally inherited mtDNA mutations (mit^- and syn^-) accelerates the accumulation of mtDNA mutations (deletions and point mutations) in somatic cells, and thereby increases the production of reactive oxygen species from mitochondria, leading to aggravation of mitochondrial diseases and degenerative changes associated with aging.

  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] A.M.V.Duncan: "Assignment of the Gene for the Cytochrome c_1 Subunit of the Mitochondrial Cyto;chrome bc_1 Complex(CYC1)to Human Chromosome 8q24.3" Genomics. 19. 400-401 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.M.Islam: "A complete cDNA sequence for core I protein subunit of human ubiquinolcytochrome c reductase" Biochem.Mol.Biol.Int.32. 797-805 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Katsumata: "Fragmentation of human heart mitochondrial DNA associated with premature aging" Biochem.Biophys.Res.Commun.202. 102-110 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Ota: "Early Retinal Involvement in Mitochondrial Myopathy with Mitochondrial DNA Delation" Retina.14. 270-276 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.M.V.Duncan: "Assignment of the gene(UQCRF51)for the Rieske iron-sulfur protein subunit of the mitochondrial cytochrome bc_1 complex to the 22q13 and 19q12-q13.1regions of the human genome" Genomics. 21. 281-283 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Tanaka: "Strand asymmetry in human mitochondrial DNA mutations" Genomics. 22. 327-335 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] W.Sato: "Cardiomyopathy and Angiopathy in Patients with Mitochondrial Myopathy,Lactic Acidosis and Stroke-like Episodes" Am.Heart J.128. 733-741 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Hayakawa: "Fragmentation of human heart mitochondrial DNA associated with premature aging" J.Mol.Cell.Cardiol. 26. CCXXI (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sergei.A.Kovalenko: "A common not spot for somatic and germline mutations in rat mitochondrial DNA:Analysis by fluorescence-based sscp" Biochem.Mol.Biol.Int.34. 1205-1214 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Furui: "Decrease in Cytochrome c Oxidase and Cytochrome Oxidase Subunit I Messenger Ribonucleic Acid Levels in Preeclamptic Pregnancies" Obstet.Gynecol. 84. 283-288 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.A.Kovalenco: "Simple methods for preparation of plasmid DNA yielding long and accurate sequence data" Nucleic Acids Research. 22. 5771-5772 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Ozawa: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Ikebe: "Point Mutations of Mitochondrial Genome in Parkinson's Disease" Mol.Brain.Res.28. 281-295 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Tanaka: "Mitochondrial DNA mutations in cardiomyopathy:combination of replacements yielding cysteine residues and tRNA mutations" Muscle and Nerve. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Ozawa: "Genotype and phenotype of a severe mitochondrial cardiomyopathy:a recipient of heart transplantation and tne genetic control" Biochem.Biophys.Res.Commun.(accepted).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.M.V.Duncan: "Assignment of the Gene for the Cytochrome c_1 Subunit of the Mitochondrial Cytochrome bc_1 Complex (CYC1) to Human Chromosome 8q24.3" Genomics. 19. 400-401 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Katsumata: "Fragmentation of human heart mitochondrial DNA associated with premature aging" Biochem.Biophys.Res.Commun.202. 102-110 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.M.V.Duncan: "Assignment of the gene (UQCRF51) for the Rieske iron-sulfur protein subunit of the mitochondrial cytochrome bc_1 complex to the 22q13 and 19q12-q13.1 regions of the human genome" Genomics. 21. 281-283 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Tanaka: "Stand asymmetry in human mitochondrial DNA mutations" Genomics. 22. 327-335 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] W.Sato: "Cardiomyopathy and Angiopathy in Patients with Mitochondrial Myopathy, Lactic Acidosis and Stroke-like Episodes" Am.Heart J. 128. 733-741 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Hayakawa: "Fragmentation of human heart mitochondrial DNA associated with premature aging" J.Mol.Cell.Cardiol. 26, CCXXI. (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sergei.A.Kovalenko: "A common hot spot for somatic and germline mutations in rat mitochondrial DNA : Analysis by fluorescence-based sscp" Biochem.Mol.Biol.Int. 34. 1205-1214 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.A.Kovalenco: "Simple methods for preparation of plasmid DNA yielding long and accurate sequence data" Nucleic Acids Reaserch. 22. 5771-5772 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Ozawa: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Tanaka: "Mitochondrial DNA mutations in cardiomyopathy : combination of replacements yielding cysteine residues and tRNA mutations" Muscle and Nerve. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Ozawa: "Genotype and phenotype of a severe mitochondrial cardiomyopathy : a recipient of heart transplantation and the genetic control" Biochem.Biophys.Res.Commun.(accepted).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1996-04-15  

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