Chronic Ethanol Feeding and the Mitochondrial Ribosomal Proteins

描述（由申请人提供）：线粒体包含自己的基因组，该基因组编码许多组成电子传递链（ETC）多肽。这些蛋白质在线粒体内的核糖体上被翻译，核糖体由线粒体编码的rRNA分子和核编码的核糖体蛋白组装而成。我们的研究表明，长期摄入乙醇会导致线粒体核糖体的错误组装，从而损害雄性大鼠肝脏线粒体蛋白的合成。具体来说，这表现为完整核糖体沉降系数的降低，未组装核糖体亚基水平的增加以及与核糖体相关的特定蛋白（MRPs）水平的改变。这伴随着线粒体呼吸受损，并导致ETC复合物水平和活动的有害改变。提出的研究旨在调查这样一种假设，即在酒精动物中发现的肝线粒体糖体功能障碍是由于特定MRPs表达缺陷引起的线粒体糖体组装损伤。具体来说，我们将(i)鉴定对亚基-亚基关联至关重要的MRP蛋白和MRP- rRNA关联；（ii）鉴定对乙醇诱导的减少特别敏感的MRP； （iii）鉴定可能参与控制MRP表达的转录因子，特别关注乙醇反应性MRP基因。希望这些研究能够阐明乙醇介导的线粒体蛋白合成损伤的分子机制，并进一步帮助我们了解酒精性肝病进展的早期阶段。酒精性肝病（ALD）是严重危害公众健康的疾病。仅在美国，肝硬化是青壮年死亡的第七大原因。每年约有10,000至24,000例肝硬化死亡可归因于饮酒。

DESCRIPTION (provided by applicant): Mitochondria contain their own genome that encodes a number of constitutive electron transport chain (ETC) polypeptides. The proteins are translated inside the mitochondria on ribosomes that are assembled from mitochondrially-encoded rRNA molecules and nuclear-encoded ribosomal proteins. Our studies have shown that chronic ethanol consumption impairs hepatic mitochondrial protein synthesis in male rats by causing the faulty assembly of mitochondrial ribosomes. Specifically, this manifests itself as a decrease in the sedimentation coefficient of intact ribosomes, an increase in the levels of unassembled ribosomal subunits and an alteration in the levels of specific proteins (MRPs) associated with the mitoribosome. This is accompanied by impaired mitochondrial respiration and leads to detrimental alterations in the levels and activities of ETC complexes. The proposed studies are designed to investigate the hypothesis that malfunction of the hepatic mitoribosomes seen in alcoholic animals is due to a lesion in mitoribosome assembly that is caused by defects in the expression of specific MRPs. Specifically, we will (i) identify MRP-protein and MRP- rRNA associations that are essential for subunit-subunit associations (ii) identify MRPs that are specifically susceptible to ethanol-elicited decreases and (iii) identify transcription factors likely to be involved in the control of MRP expression with particular focus upon ethanol-responsive MRP genes. It is hoped that these studies will elucidate the molecular mechanism(s) responsible for the ethanol-mediated impairment in mitochondrial protein synthesis and to further aid in out understanding of the early stages in the progression of alcoholic liver disease. Alcoholic liver disease (ALD) represents a serious hazard to public health. In the United States alone, cirrhosis is the seventh leading cause of death among young and middle-age adults. Approximately 10,000 to 24,000 deaths from cirrhosis may be attributable to alcohol consumption each year.