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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
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥29,000,000 (Direct Cost: ¥29,000,000)
Fiscal Year 1994: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1993: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1992: ¥19,000,000 (Direct Cost: ¥19,000,000)
Keywordsmitochondrial DNA / 8-hydroxydeoxyguanosine / aging / point mutations / oxidative stress / cardiomyopathy / deleted mtDNA / reactive oxygen species / 遺伝子欠失 / 蛍光PCR-SSCP法 / 発癌物質 / 心毒性 / ミトコンドリア病 / 老化 / 酸化的DNA損傷 / ラジカル脆弱性
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.

Report

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

    (56 results)

All Other

All Publications (56 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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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
    • Related Report
      1994 Final Research Report Summary
  • [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)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.M.Islam: "A complete cDNA sequence for core I protein subunit of human ubiquinol-cytochrome creductase" Biochem.Mol.biol.Int.32. 797-805 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] k.katsumata: "Fragmentation of human heart mitochondrial DNA associated with premature aging" Biochem.Biophys.Res.Commun.202. 102-110 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Ota: "Early Retinal Involvement in Mitochondrial Myopathy with Mitochondrial DNA Delation" Retina.14. 270-276 (1994)

    • Related Report
      1994 Annual Research Report
  • [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" Cenomics. 21. 281-283 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Tanaka: "Strand asymmetry in human mitochondrial DNA mutations" Genomics. 22. 327-335 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] W.Sato: "Cardiomyopathy and Angiopathy in Patients with Mitochondrial Myopathy,Lactic Acidosis and Stroke-like Episodes" Am.Heart J.128. 733-741 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Hayakawa: "Fragmentation of human heart mitochondrial DNA associated with premature aging" J.Mol.Cell.Cardiol.26. CCXXI (1994)

    • Related Report
      1994 Annual Research Report
  • [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)

    • Related Report
      1994 Annual Research Report
  • [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)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.A.Kovalenco: "Simple methods for preparation of plasmid DNA yielding long and accurate sequence data" Nucleic Acids Research. 22. 5771-5772 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] T.Ozawa: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.Ikebe: "Point Mutations of Mitochondrial Genome in Parkinson's Disease" Mol.Brain.Res.28. 281-295 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Tanaka: "Mitochondrial DNA mutations in cardiomyopathy:combination of replacements yielding cysteine residues and tRNA mutations" Muscle and Nerve. (in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [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). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Hayakawa: "Age-associated Damage in Mitochondrial DNA in Human Hearts" Mol.Cell.Biochem.119. 95-103 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] M.Takasawa: "Age-associated damage in mitochondrial function in rat hearts" Exp Gerontol. 28. 269-280 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Sugiyama: "Detrimental Effects of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine,a Mutagenic Agent,on Mitochondrial Respiration among Various Rat Tissues" Biochem.Mol.Biol.Int.30. 797-805 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Sugiyama: "Changes in Skeletal Muscle,Heart and Liver Mitochondrial Electron Tranport Activities in Rats and Dogs of Various Ages" Biochem.Mol.Biol.Int.30. 937-944 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Mizuno: "Mitochondrial energy crisis in Parkinson's disease." Adv Neurol. 60. 282-7 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Ito: "Mitochondrial DNA mutations in cardiomyopathy." Jpn Circ J. 56. 1045-53 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Kanai: "Mitochondrial dysfunction in the non-obstructed lobe of rat liver after selective biliary obstruction." Hepatogastroenterology. 39. 385-91 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Obayashi: "Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyofpthy." Am.Heart J.24. 1263-1269 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Sahashi: "Increased mitochondrial DNA deletions in the skeletal muscle of myotonic dystrophy." Gerontology. 38. 18-29 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Torii: "Aging-associated deletions of human diaphragmatic mitochondrial DNA." Am J Respir Cell Mol Biol. 6. 543-9 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Yamamoto: "Significant existence of deleted mitochondrial DAN in cirrhotic liver surrounding hepatic tumor." Biochem Biophys Res Commun. 182. 913-20 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hayakawa M.: "Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts." Biochem.Biophys.Res.Commun.189. 979-985 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hayakawa M.: "Age-associated damage in mitochondrial DNA in human hearts." Mol.Cell.Biochem.

    • Related Report
      1992 Annual Research Report
  • [Publications] Hayakawa M.: "Conversion of deoxygyanosine into 8-hydroxydeoxyguanosine in mouse liver mitochondrial DNA by administration of azidothymidine." Immunigherapy.

    • Related Report
      1992 Annual Research Report
  • [Publications] Takasawa M.: "Age-accociated damage in mitochondrial function in rat hearts." Exp.Gerontol.

    • Related Report
      1992 Annual Research Report

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

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