Mitochondrial voltage-dependent anion channel is responsible for paraquat cytotoxicity.

线粒体电压依赖性阴离子通道是百草枯细胞毒性的原因。

• 批准号: 17591899
• 负责人: SHIMADA Hiroki
• 金额: $ 2.18万
• 依托单位: KANAZAWA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591899/
• 关键词: paraquat; mitochondria; cytotoxicity; NADH-quinone oxidoreductasem; voltage-dependent anion channel; superoxide; hydrogen peroxide; NADH; voltage-dependent anion channel; NADH-quinone oxidoreductase_m; permeability transition pore

Paraquat is an herbicide that forms reactive oxygen metabolites, which are toxic to humans. With respect to the cytotoxicmechanisms, we identified a NADH-quinone oxidoreductasem activity located on the mitochondria and propose the participationof a voltage-dependent anion channel, VDAC.When isolated rat mitochondria were incubated with NADH and paraquat, H_2O_2 was produced by NADH-quinoneoxidoreductasem activity of the outer membrane and the mitochondria were damaged. These changes were suppressed bybenzoquinone, 4,4'-diisothiocyanatostilbene-2,29-disulfic acid and anti-VDAC1 antibody. NADH-quinone oxidoreductasemactivity was located by zymography at the 500kDa band on native-polyacrylamide electrophoresis, and it contained VDAC protein in a Western blot. VDAC1-overexpressed HeLa cells treated with paraquat produced more intracellular H_2O_2 thancontrols and were more sensitive to paraquat. In contrast, mitochondria in VDAC1 knockdown cells did not produce H_2O_2 andhad a higher survival rate after exposure to paraquat. The results indicate that mitochondrial VDAC protein was associated with reactive oxygen species that mediated paraquat toxicity.

百草枯是一种除草剂，会形成活性氧代谢物，对人体有毒。关于细胞毒性机制，我们鉴定了位于线粒体上的NADH-醌氧化还原酶活性，并提出电压依赖性阴离子通道VDAC的参与。当分离的大鼠线粒体与NADH和百草枯一起孵育时，NADH-醌氧化还原酶活性产生H_2O_2外膜和线粒体受损。这些变化被苯醌、4,4'-二异硫氰酸二苯乙烯-2,29-二硫酸和抗 VDAC1 抗体抑制。通过酶谱法将 NADH-醌氧化还原酶活性定位在天然聚丙烯酰胺电泳的 500kDa 条带处，并且在蛋白质印迹中含有 VDAC 蛋白。用百草枯处理的VDAC1过表达的HeLa细胞比对照组产生更多的细胞内H_2O_2，并且对百草枯更敏感。相比之下，VDAC1敲低细胞中的线粒体在接触百草枯后不产生H_2O_2并且具有更高的存活率。结果表明，线粒体 VDAC 蛋白与介导百草枯毒性的活性氧相关。

项目成果

Furanonaphthoquinones Cause Apoptosis of Cancer Cells by Inducing the Production of Reactive Oxygen Species by the Mitochordrial Voltage-Dependent Anion Channel

呋喃萘醌通过诱导线粒体电压依赖性阴离子通道产生活性氧，导致癌细胞凋亡

• 发表时间: 2006
• 期刊: Cancer Biology ＆ Therapy 5・11
• 作者: Simamura;E.
• 通讯作者: E.

Furanonaphthoquinones Cause Apoptosis of Cancer Cells by Inducing the Production of Reactive Oxygen Species by the Mitochondrial Voltage-Dependent Anion Channel

呋喃萘醌通过诱导线粒体电压依赖性阴离子通道产生活性氧，导致癌细胞凋亡

• 发表时间: 2006
• 期刊: Cancer Biology ＆ Therapy 5
• 作者: Simamura;E.
• 通讯作者: E.