CHRONIC ETHANOL CONSUMPTION AND MITOCHONDRIAL DNA DAMAGE

长期乙醇消耗与线粒体 DNA 损伤

• 批准号: 6044922
• 负责人: ALAN CAHILL
• 金额: $ 20.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-19 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044922
• 关键词: DNA damage; adduct; age difference; alcoholic beverage consumption; alcoholism /alcohol abuse; ethanol; laboratory rat; mitochondrial DNA; oxidative stress; pathologic process; phosphorylation

DESCRIPTION: (Adapted from the Investigator's Abstract) It is proposed to investigate the hypothesis that chronic ethanol consumption results in increased oxidative damage to mtDNA and that aging may increase the susceptibility of liver mitochondria to ethanol-elicited defects in mtDNA homeostasis. Published data show that long-term ethanol feeding has a profound effect on the metabolic functioning of rat liver mitochondria. Ethanol intake results in decreased oxidative phosphorylation, structurally abnormal mitochondria and elevated levels of mitochondrially-produced reactive oxygen species. Previous studies by the investigator have established that long term exposure causes increased oxidative damage to mtDNA, as reflected by increased levels of 8-hydroxydeoxyguanosine (8-OHdG) adducts. These studies have been extended to show that 2 month old animals maintained on the Lieber-DeCarli diet for one year exhibit a 40% depletion in mtDNA content and a 3-fold increase in 8-OHdG adduct formation. In addition, increases in single strand breaks and deletions of mtDNA are also observed. Recently, a short term, chronic ethanol feeding regimen was developed where 1 year old rats are fed the Lieber-DeCarli diet for 2 months, a feeding period that is not associated with alterations in mtDNA structure in young animals. Preliminary results show that these animals exhibit a greater mtDNA depletion (greater than 60%) than that seen in young animals fed ethanol for 1 year. This suggests that aging increases the susceptibility of hepatic mitochondria to ethanol-induced alterations in mtDNA homeostasis. The proposed studies will (a) fully characterize the new feeding model with regard to mtDNA content, levels of oxidative damage and the activities of respiratory chain complexes; (b) investigate the effect of oxidative damage on the processes of mtDNA degradation and repair in old animals, in order to elucidate the biochemical mechanism(s) behind the ethanol-elicited mtDNA depletion; (c) investigate the role of ethanol and reactive oxygen species in the formation of mtDNA deletions; (d) investigate the effect of decreased mtDNA content on the production of mitochondrial transcripts and the activities of electron transport chain complexes; (e) investigate the role of mtDNA structural alterations in the formation of pathological lesions associated with alcoholic liver disease (ALD); and (f) investigate the effects of ethanol consumption on hepatic mtDNA structure in human alcoholics. Our understanding of the role of mtDNA in the pathogenesis of alcoholic liver disease will be enhanced by these in-depth analyses.

描述：(改编自《调查员摘要》)建议 调查长期饮酒会导致 线粒体DNA的氧化损伤增加，衰老可能会增加 肝线粒体对乙醇引起的线粒体DNA缺陷的易感性 动态平衡。已公布的数据显示，长期喂食乙醇具有深远的影响 对大鼠肝线粒体代谢功能的影响。酒精摄入量 导致氧化磷酸化降低，结构异常 线粒体与线粒体产生的活性氧水平升高 物种。研究人员之前的研究已经证实了这种长期的 暴露导致线粒体DNA氧化损伤增加，这反映在 8-羟基脱氧鸟苷(8-OHdG)加合物水平。这些研究一直是 延伸到表明2个月大的动物保持在Lieber-DeCarli饮食中 一年内线粒体DNA含量减少40%，而 8-OHdG加合物形成。此外，单链断裂的增加和 同时还观察到线粒体DNA的缺失。最近，一种短期、慢性的乙醇 1岁的大鼠喂食利伯-德卡利的饲喂方案被开发出来 2个月的饮食，这段喂食期与 幼年动物的线粒体DNA结构。初步结果显示，这些动物 表现出比年轻人更大的线粒体DNA耗竭(超过60%) 动物饲喂乙醇1年。这表明，衰老会增加 肝线粒体对乙醇引起的线粒体DNA改变的敏感性 动态平衡。拟议的研究将(A)充分描述新的喂养方式。 关于线粒体DNA含量、氧化损伤水平和 呼吸链复合体的活性；(B)调查 氧化损伤对老年人线粒体DNA降解修复过程的影响 动物，为了阐明背后的生化机制(S) 乙醇引起的线粒体DNA枯竭；(C)调查乙醇和 线粒体DNA缺失形成过程中的活性氧物种；(D)调查 线粒体DNA含量降低对线粒体产生的影响 转录本和电子传递链复合体的活性；(E) 探讨线粒体DNA结构改变在骨肉瘤形成过程中的作用 与酒精性肝病有关的病理损害；及(F) 探讨酒精摄入对小鼠肝脏线粒体DNA结构的影响 人类酗酒者。我们对线粒体DNA在骨肉瘤发病机制中作用的认识 通过这些深入的分析，酒精性肝病将得到加强。