低剂量铜暴露抑制ALS小鼠延髓线粒体自噬  

Low-dose copper exposure inhibited mitophagy in medulla oblongata of ALS mice

作　　者：张欢 杨晓 高川月 杨细飞 ZHANG Huan;YANG Xiao;GAO Chuanyue;YANG Xifei(School of Public Health,Hengyang Medical School,University of South China,Hengyang 421001,Hunan,China;Shenzhen Key Laboratory of Modern Toxicology,Key Discipline of Health Toxicology,Shenzhen Center for Disease Control and Prevention,Shenzhen 518055,Guangdong,China;School of Public Health,Shanxi Medical University,Taiyuan 030001,Shanxi,China)

机构地区：[1]南华大学衡阳医学院公共卫生学院,湖南衡阳421001 [2]深圳市疾病预防控制中心,深圳市现代毒理学重点实验室深圳市卫生毒理学医学重点学科,广东深圳518055 [3]山西医科大学公共卫生学院,山西太原030001

出　　处：《中南医学科学杂志》2023年第4期486-491,共6页Medical Science Journal of Central South China

基　　金：国家自然科学基金项目(82171583);深圳市科技创新委员会重点基础研究计划项目(JCYJ20200109150717745XY,JCYJ20200109144418639);深圳香港脑科学研究所-深圳基础研究项目(NYKFKT20190019);深圳市医学重点学科建设经费资助(SZXK069);深圳市医疗卫生“三名工程”项目(SZSM201611090)。

摘　　要：目的基于生物信息学分析低剂量铜(Cu)暴露对肌萎缩侧索硬化症(ALS)延髓线粒体自噬的影响。方法将24只小鼠均分为正常对照组(WT组)、模型组(ALS组)、铜暴露组(ALS+Cu组)、铜暴露尿石素A干预组(ALS+Cu+UA组)。动物取材后收集各组小鼠延髓组织,采用TMT-labeled蛋白质组学分析Cu暴露对ALS小鼠延髓线粒体相关生物学过程的影响,蛋白免疫印迹检测线粒体自噬相关信号分子的水平。结果与WT组相比,ALS组小鼠延髓中氧化磷酸化、自噬和突触相关生物学过程的蛋白表达水平均下调,Parkin、ATG7、Ndufa10、Atp5a、ATG5、Lamp1、Pink1、Beclin1、Ctsd的表达水平也显著降低;而Cu暴露进一步加重ALS组小鼠延髓中上述生物学过程相关蛋白和线粒体自噬相关蛋白的下调。UA干预可以上调ALS铜暴露小鼠延髓中上述线粒体相关蛋白水平。结论Cu暴露可能通过抑制线粒体自噬,促进ALS的进展。Aim To use bioinformatics to analyze the effect of low-dose copper(Cu)exposure on the medulla oblongata in amyotrophic lateral sclerosis(ALS).Methods Twenty-four mice were divided into normal control group(WT group),model group(ALS group),Cu exposure group(ALS+Cu group)and Cu exposure with urolithin A intervention group(ALS+Cu+UA group).The medullary tissue of mice in each group was collected after animal sampling,the effects of Cu exposure on mitochondrial related biological processes in ALS mice were analyzed with TMT-labeled proteomics,and the levels of mitophagy related signaling molecules were detected by Western blotting.Results Compared with WT group,the proteins related to oxidative phosphorylation,autophagy and synaptic biological processes were down-regulated in the medullae oblongata of mice in ALS model group,and the expression levels of Parkin,ATG7,Ndufa10,Atp5a,ATG5,Lamp1,Pink1,Beclin1 and Ctsd were significantly decreased.Cu exposure further aggravated the down-regulation of the proteins related the above biological process and mitophagy in the medulla oblongata of ALS model group.UA intervention up-regulated the above mitochondria-related changes in the medulla oblongata of Cu-exposed ALS mice.Conclusion Cu exposure might cause ALS progression via inhibiting mitophagy.

关 键 词：肌萎缩侧索硬化症 铜暴露 蛋白质组学 线粒体自噬 生物信息学分析 

分 类 号：R3[医药卫生—基础医学]