1994 Fiscal Year Annual Research Report

老化およびミトコンドリア病に係わるミトコンドリア遺伝子変異

Research Project

Project/Area Number	04404029
Research Institution	Nagoya University
Principal Investigator	小澤高将名古屋大学, 医学部, 教授 (80022771)
Co-Investigator(Kenkyū-buntansha)	早川美佳名古屋大学, 医学部, 助手 (10238090) 田中雅嗣名古屋大学, 医学部, 助教授 (60155166)
Keywords	ミトコンドリアDNA / 8-hydroxydeoxyguanosine / 加齢 / 点変異 / 酸化ストレス / 心筋症 / 欠失mtDNA / 活性酸素
Research Abstract	ミトコンドリアは細胞における酸素代謝の主要な場である。呼吸に伴って発生する活性酸素ラジカルが、mtDNA自信の損傷を引き起こしうる。活性酸素ラジカルによるmtDNAの損傷とこれに伴う変異蓄積の、ミトコンドリア病および加齢に伴う病変への関与を検証した。多数例についてmtDNAの全塩基配列を解析した結果、mRNA遺伝子における種間保存されているアミノ酸の置換を伴う塩基置換(mit^-)に加えて、tRNA・rRNA遺伝子における種間保存されている部位の塩基置換(syn^-)を複合して有する患者の死亡年齢が、mit-変異のみ、あるいはsyn-変異のみを有する患者の死亡年齢より有為に低いことを見いだした(Lancet 345:189,1995)。ヒト剖検心筋において欠失mtDNAと8-OH-dGの両者が加齢と共に蓄積し、指数関数的に増加することを示した(BBRC189:979-85,1992)。180組のプライマーを用いてmtDNA欠失を網羅的に検出する系を用いて、mit^-変異とsyn^-変異を伴った心筋症の19歳の患者で欠失mtDNAが高齢者において検出される量に匹敵する量に達していることを明らかにした(BBRC202:102-110,1995)。7歳で心臓移植を受けた患者において3種の生殖腺細胞変異に加えて、212種の欠失mtDNAを体細胞変異として検出し、表現型とmtDNA遺伝子型の間の関連を明確にした(BBRC207:613-620,1995)。高酸素下で誘発される細胞死に欠失mtDNAの増加が伴うことを示した(BBRC in press)。母系遺伝によって伝えられたmtDNA変異(mit^-およびsyn^-変異)が複合し、さらに後天的にmtDNAに蓄積する点変異および欠失がこれらに加わり、活性酸素ラジカルによるmtDNAの損傷を加速していることが明らかにした。

Research Products

(15 results)

All Other

All Publications (15 results)

[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)
[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)
[Publications] k.katsumata: "Fragmentation of human heart mitochondrial DNA associated with premature aging" Biochem.Biophys.Res.Commun.202. 102-110 (1994)
[Publications] Y.Ota: "Early Retinal Involvement in Mitochondrial Myopathy with Mitochondrial DNA Delation" Retina.14. 270-276 (1994)
[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)
[Publications] M.Tanaka: "Strand asymmetry in human mitochondrial DNA mutations" Genomics. 22. 327-335 (1994)
[Publications] W.Sato: "Cardiomyopathy and Angiopathy in Patients with Mitochondrial Myopathy,Lactic Acidosis and Stroke-like Episodes" Am.Heart J.128. 733-741 (1994)
[Publications] M.Hayakawa: "Fragmentation of human heart mitochondrial DNA associated with premature aging" J.Mol.Cell.Cardiol.26. CCXXI (1994)
[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)
[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)
[Publications] S.A.Kovalenco: "Simple methods for preparation of plasmid DNA yielding long and accurate sequence data" Nucleic Acids Research. 22. 5771-5772 (1994)
[Publications] T.Ozawa: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)
[Publications] S.Ikebe: "Point Mutations of Mitochondrial Genome in Parkinson's Disease" Mol.Brain.Res.28. 281-295 (1995)
[Publications] M.Tanaka: "Mitochondrial DNA mutations in cardiomyopathy:combination of replacements yielding cysteine residues and tRNA mutations" Muscle and Nerve. (in press). (1995)
[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)

1994 Fiscal Year Annual Research Report

老化およびミトコンドリア病に係わるミトコンドリア遺伝子変異

Principal Investigator

小澤 高将 名古屋大学, 医学部, 教授 (80022771)

Research Products

[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)

[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)

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

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

[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)

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

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

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

[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)

[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)

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

[Publications] T.Ozawa: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)

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

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

[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)

小澤高将名古屋大学, 医学部, 教授 (80022771)