Mechanism of cytotoxicity of psychosine
| Project/Area Number |
61570393
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurology
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| Research Institution | University of Occupational and Environmental Health |
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Principal Investigator |
IGISU Hideki University of Occupational and Environmental Health, 医学部, 助教授 (60108686)
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| Project Period (FY) |
1986 – 1987
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| Project Status |
Completed (Fiscal Year 1987)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1987: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1986: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Psychosine / Galactosylsphingosine / Krabbe disease / Mitochondria / シトクロームCオキシダーゼ |
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| 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.
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Report
(2 results)
Research Products
(7 results)
