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Mitochondrial oxidoreductase of outer membrane is responsible for paraquat cytotoxicity

Research Project

Project/Area Number 15591664
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionKANAZAWA MEDICAL UNIVERSITY

Principal Investigator

SHIMADA Hiroki  Kanazawa Medical University, Molecular and Cell Structural Science, 医学部, 講師 (60278108)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsparaquat / mitochondria / NADH-quinone oxidoreductase_m / superoxide / voltage-dependent anion channel / permeability transition pore / herbicide
Research Abstract

The acute toxicity of paraquat (PQ), which is a widely used herbicide in agriculture and believed to be a risk factor of Parkinson's disease, is mediated by reactive oxygen species (ROS) produced by their cyclic oxidation-reduction reaction and causes severe injury to the lungs and other multiorgans in mammals. It has generally been speculated that NADPH-cytochrome P450 reductase in the microsomal drug-metabolizing enzyme systems formed ROS as the in vitro toxic mechanisms. Recently, we demonstrated that the ROS were formed from the outer surface of the mitochondria (Mt) in the presence of cytoplasmic NADH and injured the Mt. As for the mechanisms, we have found an NADH-quinone oxidoreductase_m (NQO_m) activity located on the outer membrane of Mt and propose the participation of voltage dependent anion channel (VDAC).
When isolated rat Mt were incubated with 2', 7'-dichlorofluorescin-diacetate, a fluorescent probe of H_2O_2 production, control Mt showed a faint fluorescence due to the formation of 2', 7'-dichlorofluorescein. An addition of NADH or PQ alone did not change the intensity, but coexistence of NADH and PQ raised it. The intensity was suppressed by benzoquinone, a scavenger of O_2^- and decreased by voltage dependent anion channel (VDAC) inhibitors and anti-VDAC antibody.
After the starvation, almost all of the Mt appeared to be orthodox and condensed conformation. When PQ and NADH were added simultaneously, swollen and broken Mt were markedly increased. Anti-VDAC antibody inhibited the damage.
NQO_m activity as NADH dependent PQ reduction was observed by the reduction of nitroblue tetrazolium (NBT) in the detergent-extract of the outer membrane. It was suppressed by anti-VDAC antibody, DIDS and DCCD. The activity was positive at the 500 kDa band by zymography on native-PAGE using NBT reduction. This band contained VDAC protein determined by Western blot.
These results indicate that VDAC protein may cause PQ toxicity.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (12 results)

All 2004 2003

All Journal Article (12 results)

  • [Journal Article] The participation of voltage dependent anion channel (VDAC) protein in NADH-quinone oxidoreductase_m activity on paraquat cytotoxicity2004

    • Author(s)
      H, Shimada, et al.
    • Journal Title

      8th Asia-Pacific Conference on Electron Microscopy, 2004 PROC

      Pages: 1229-1230

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The participation of mitochondrial membrane permeable protein in mitochondrial damage by an anticancer agent furanonaphthoquinone2004

    • Author(s)
      E, Simamura, et al.
    • Journal Title

      8th Asia-Pacific Conference on Electron Microscopy, 2004 PROC

      Pages: 1274-1275

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ミトコンドリア膜透過性タンパクによるフラノナフトキノン誘導体の活性酸素生成2004

    • Author(s)
      島村英理子, 他
    • Journal Title

      第4回ミトコンドリア研究会年会要旨集

      Pages: 26-26

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The participation of voltage dependent anion channel (VDAC) protein in NADH-quinone oxidoreductase_m activity on paraquat cytotoxicity2004

    • Author(s)
      Hiroki Shimada, et al.
    • Journal Title

      Proceedings of 8th Asia-Pacific Conference on Electron Microscopy

      Pages: 1229-1230

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The participation of mitochondrial membrane permeable protein in mitochondrial damage by an anticancer agent furanonaphthoquinone2004

    • Author(s)
      E, Simamura, et al.
    • Journal Title

      Proceedings of 8th Asia-Pacific Conference on Electron Microscopy

      Pages: 1325-1326

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The participation of voltage dependent anion channel (VDAC) protein in NADH-quinone oxidoreductase_m activity on paraquat cytotoxicity2004

    • Author(s)
      Hiroki Shimada
    • Journal Title

      Proceedings of 8th Asia-Pacific Conference on Electron Microscopy

      Pages: 1231-1232

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung cancer cells2003

    • Author(s)
      E, Simamura, et al.
    • Journal Title

      Cancer Detect.Prev 27

      Pages: 5-13

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ペラコートのミトコンドリア毒性に関与する膜透過性タンパク質の蛍光画像解析2003

    • Author(s)
      島田ひろき, 他
    • Journal Title

      電子顕微鏡(日本顕微鏡学会第59回学術講演会プロシーディングス) 38(補1)

      Pages: 200-200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] パラコートのミトコンドリア障害に対するミトコンドリア膜透過性蛋白の関与2003

    • Author(s)
      島村英理子, 他
    • Journal Title

      電子顕微鏡(日本顕微鏡学会第59回学術講演会プロシーディングス) 38(補1)

      Pages: 199-199

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] パラコート細胞毒性に関与するNADH-quinone oxidoreductasem活性の探求2003

    • Author(s)
      島田ひろき, 他
    • Journal Title

      第3回ミトコンドリア研究会年会要旨集

      Pages: 60-60

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ミトコンドリアを標的とする抗腫瘍物質フラノナフトキノン誘導体の研究2003

    • Author(s)
      島村英理子, 他
    • Journal Title

      第3回ミトコンドリア研究会年会要旨集

      Pages: 29-29

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung cancer cells2003

    • Author(s)
      E, Simamura, et al.
    • Journal Title

      Cancer Detect.Prev. 27

      Pages: 5-13

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary

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Published: 2003-04-01   Modified: 2016-04-21  

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