Chronic Ethanol Feeding and the Mitochondrial Ribosomal Proteins

描述（由申请人提供）：线粒体含有其自身的编码许多组成型电子传递链（ETC）多肽的基因组。这些蛋白质在线粒体内的核糖体上翻译，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，慢性乙醇消耗损害肝线粒体蛋白质的合成，在雄性大鼠引起线粒体核糖体的错误组装。具体而言，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线粒体相关的特异性蛋白质（MRP）水平的改变。这伴随着受损的线粒体呼吸，并导致ETC复合物的水平和活性的有害改变。拟定的研究旨在研究以下假设：在酒精性动物中观察到的肝线粒体功能障碍是由于特定MRP表达缺陷引起的线粒体组装病变所致。具体而言，我们将（i）鉴定亚基-亚基缔合所必需的MRP-蛋白和MRP- rRNA缔合，（ii）鉴定对乙醇引起的降低特别敏感的MRP，和（iii）鉴定可能参与MRP表达控制的转录因子，特别关注乙醇响应性MRP基因。希望这些研究将阐明负责乙醇介导的线粒体蛋白质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）是一种严重危害公众健康的疾病。仅在美国，肝硬化是年轻人和中年人死亡的第七大原因。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.