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Generation and application of mtDNA knockout mice as models for mitochondrial diseases

Research Project

Project/Area Number 10358018
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Laboratory animal science
Research InstitutionUniversity of Tsukuba

Principal Investigator

HAYASHI Jun-ichi  University of Tsukuba, Institute of Biological Sciences, Professor, 生物科学系, 教授 (60142113)

Co-Investigator(Kenkyū-buntansha) GOTO Yu-ichi  National Center of Neurology and Psychiatry, National Institute of Neuroscience, Department of Mental Retardation and Birth Defect Research, 神経研究所, 部長 (20225668)
高井 大策  筑波大学, 生物科学系, 助手 (20302367)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥29,990,000 (Direct Cost: ¥28,700,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2001: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2000: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1999: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1998: ¥14,400,000 (Direct Cost: ¥14,400,000)
KeywordsMouse mtDNA / mtDNA Mutation / Mitochondrial transfer / Disease model mice / mitochondrial tRNA / mtDNA突然変異 / ミトコンドリアVRNA / マウス / ミトコンドリアDNA / 遺伝子導入 / 突然変異 / ミトコンドリア遺伝子病 / 病態モデルマウス / ミトコンドリアDNAノックアウトマウス / マウス受精卵 / マイクロインジェクション法 / 呼吸欠損株
Research Abstract

Mice possessing pathogenic mutant mitochondrial DNA (mtDNA) would provide ideal systems for studying exactly how mutant mtDNAs are transmitted and distributed in tissues resulting in expression of mitochondrial diseases, but no effective procedures are available for their generation. Isolation of mtDNA-less (ρ^0) mouse cells enabled us to trap mouse mutant mtDNAs that had accumulated in somatic tissues into mtDNA repopulated ρ^0 cells (cybrids). We could isolate respiration-deficient cybrids with a deletion mutant mtDNA and introduce it into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice unexpectedly died as a consequence of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases. Escape ofJhe tissues with up to 90 % mutant mtDNA from expression of disease phenotypes was enabled by the extensive intermitochondrial interaction.

Report

(5 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Tomoko Ono: "Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria"Nature Genet. 28. 272-275 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroshi Shitara: "Non-invasive visualization of sperm mitochondrial behavior in trausgenic mice with introduced green fluorescent protein (GFP)"FEBS Lett.. 500. 7-11 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kazuto Nakada: "Inter-mitochondrial complementation : mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA"Nature Med.. 7. 934-939 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 井上貴美子: "病原性突然変異mtDNA導入によるミトコンドリア疾患モデルマウスの作成"蛋白質 核酸 酵素. 46. 829-837 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 磯部ことよ: "ミトコンドリア連携説:ヒトはミトコンドリア間情報交換によって呼吸機能不全を回避する"実験医学. 19. 2198-2201 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 中田和人: "ミトコンドリア遺伝子疾患を阻止するミトコンドリア間相互作用"細胞工学. 20. 1552-1565 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomoko Ono: "Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria"Nature Genet. 28. 272-275 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroshi Shitara: "Non-invasive visualization of sperm mitochondria behavior in transgenic mice with introduced green fluorescent protein (GFP)"FEBS Lett. 500. 7-11 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kazuto Nakada: "Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA"Nature Med. 7. 934-939 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kimiko Inoue: "Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes"Protein Nucleic Acid and Enzyme. 46:. 829-837

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kotoyo Isobe: "Interaction theory of mitochondria: protection of human subjects from mitochondrial dysfunction by continuous exchange of mtDNA products between mitochondria"Experimental Medicine. 19. 2198-2201 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kazuto Nakada: "Mitochondria-specific system preventing expression of disease phenotypes by mutant mtDNA"Cell Technology. 20. 1552-1565 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomoko Ono: "Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria"Nature Genet.. 28. 272-275 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroshi Shitara: "Non-invasive visualization of sperm mitochondria behavior in transgenic mice with introduced green fluorescent protein (GFP)"FEBS Lett.. 500. 7-11 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kazuto Nakada: "Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA"Nature Med.. 7. 934-939 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 井上貴美子: "病原性突然変異mtDNA導入によるミトコンドリア疾患モデルマウスの作製"蛋白質核酸酵素. 46. 829-837 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 磯部ことよ: "ミトコンドリア連携説:ヒトはミトコンドリア間情報交換によって呼吸機能不全を回避する"実験医学. 19. 2198-2201 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 中田和人: "ミトコンドリア遺伝子疾患を阻止するミトコンドリア間相互作用"細胞工学. 20. 1552-1565 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Makiko Yamaoka: "Complete repopulation of mouse mtDNA-less cells with rat mtDNA restores mitochondrial translation but not respiratory function"Genetics. 155. 301-307 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masato Tawata: "A new mtDNA mutation at 14577 T/C is probably a major pathogenic mutation of matemally inherited type 2 diabetes"Diabetes. 49. 1269-1272 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiroshi Shitara: "Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from livercells, occurs throughout"Genetics. 156. 1277-1284 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kimiko Inoue: "Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes"Nature Genetics. 26. 176-181 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Eizo Ohkubo: "A patient with type 2 diabetes mellitus associated with mutations in sensing receptor gene and mitochondrial DNA"Biochem.Biophys.Res.Commun.. 278. 808-813 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yuko Aomi: "Cytoplasmic transfer of platelet mtDNA from eldery patients with Parkinson's disease to mtDNA-less Hela cells restores complete mitochondrial respiratory function"Biochom.Biophys.Res.Commun. 280. 265-273 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamaoka,M.: "Complete repopulation of mouse mitochondrial DNA-less cells with rat mitochondrial DNA restores mitochondrial translation but not mitochondrial respiratory function"Genetics. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ito,S.: "Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from aged patients with Alzheimer's disease."Proc.Natl.Acad.Sci.USA. 96. 2099-2103 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takai,D.: "Transcomplementation between different types of respiration-deficient mitochondria with different pathogenic mutant mitochondrial DNAs."J.Biol.Chem.. 274. 11199-11202 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsuoka,R.: "A mitochondrial DNA mutation co-segregates with the pathophysiological U wave."Biochw.Biophys.Res.Commun.. 257. 228-233 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakai,Y.: "Acute exercise causes mitochondrial DNA deletion in rat skeletal muscle."Muscle New.. 22. 258-261 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 磯部ことよ: "特集:ミトコンドリアDNA変異と疾患-ミトコンドリア呼吸機能異常の体細胞遺伝学"細胞. 31. 183-186 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊藤清香: "新ミトコンドリア学"共立出版(印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 山岡万希子: "新ミトコンドリア学"共立出版(印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hiroshi Shitara: "Matemal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked patemal mtDNA followed by the prevention of subsequent patemal leakage." Genetics. 148. 851-857 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kotoyo Isobe: "Nuclear-recessive mutations of factors involved in mitochondrial translation are responsible for age-related respiration deficiency of human skin fibroblasts" J.Biol.Chem.273. 4601-4606 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sayama Ito: "Long-term postmortem survival of mitochondrial genomes in mouse synaptosomes and their rescue in a mitochondrial DNA-less mouse cell line" Biochem.Biophys.Res.Commun.247. 432-435 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sayaka Ito: "Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from aged patients with Alzheimer's disease" Proc.Natl.Acad.Sci.USA. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Daisaku Takai: "Transcomplementation between different types of respiration-deficient mitochondria with different pathogenic mutant mitochondrial DNAs." J.Biol.Chem.(印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 磯部ことよ: "特集:ミトコンドリアDNA変異と疾患 -ミトコンドリア呼吸機能異常の体細胞遺伝学-" 細胞. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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