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1987 Fiscal Year Final Research Report Summary

Mechanism of cytotoxicity of psychosine

Research Project

Project/Area Number 61570393
Research Category

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

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionUniversity of Occupational and Environmental Health

Principal Investigator

IGISU Hideki  University of Occupational and Environmental Health, 医学部, 助教授 (60108686)

Project Period (FY) 1986 – 1987
KeywordsPsychosine / Galactosylsphingosine / Krabbe disease / Mitochondria / シトクロームCオキシダーゼ
Research Abstract

Enzymatic defect has been discovered in most sphingolipidoses including Krabbe disease (globoid cell leukodystrophy).However,how the defect of the enzyme causes the pathology has not been defined.We dound accumulation of psychosine(galactosylsphingosine),a natural substrate of the missing enzyme,in the brains affected with globoid cell leukodystrophy. Since psychosine is a potent toxin,the devastating pathology in Krabbe disease appeared to be caused by the toxic effects of the accumulated lipid(Igisu & Suzuki,Science 224,753-755). Nevertheless,the mechnism of toxicity of psychosine has not been known.The present study was undertaken to clarify this.
Using mitochondria from rat liver,we found that psychosine can exert a powerfun inhitory effect on cellular respiration(Igisu & Nakamura,Biochem.Biophys.Res.Commun.137,323-327). Pi uptake and acetoacetate formation were suppressed by psychosine and reduced form of cytochrome c increased in the reaction mixture which contained psychosine.Using reducded form of cytochrome c as substrate,less than 5 <mu>M of psychosine(0.1)<mu>mo1es/mg of mitochondrial protein)inhibited cytochrome c oxidase by 50%.Thus,psychosine inhibits cytochrome c oxidase in mitochondria.Besides,the inhibition was completely and immediately abolished upon addition of albumin(final concentration of 1%),indicating that the inhibition is reversible.
Furthermore,we found that the inhibition of cytochrome c oxidase is due to the perturbation of the environment of the enzyme in mitochondrial membrane(Igisu et al.,Lipids, in press).When the enzyme was purified,psychosine did not inhibit but mildly activated the enzyme.In contrast,when cytochrome c oxiase was"reconstituted"with sonicated phosphatidylcholine,psychosine suppressed the enzyme activity as it did in mitochondria.

  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Igisu,H.;Nakamura,M.: Biochem.Biophys.Res.Commun.137. 323-327 (1986)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Igisu,H.;et al.: Neuroscience. 22. s459 (1987)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Igisu,H.;et al.: Lipids.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Igisu,H.and Nakamura,M.: "Inhibition of Cytochrome c Oxidase by Psychosine(Galactosylsphingosine)" Biochem.Biophys.Res.Commun.137. 323-327 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Igisu,H.,Nakamura,M.,et al.: "Cytotoxicity of Galacto-and Glucopsychosine:Reversible Inhibition of Cytochrome c Oxidase." Neuroscience. 22. 459 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Igisu,H.,Hamasaki,N.,et al.: "Inhibition of Cytochrome c Oxidase and Hemolysis Caused by Lysosphingolipids." Lipids.

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

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Published: 1989-03-30  

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