Chronic Ethanol Feeding and the Mitochondrial Ribosomal Proteins

描述(申请人提供)：线粒体包含它们自己的基因组，编码一些构成电子传输链(ETC)的多肽。这些蛋白质被翻译到线粒体内的核糖体上，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，慢性酒精摄入通过导致线粒体核糖体的错误组装，损害了雄性大鼠肝脏线粒体蛋白质的合成。具体地说，这表现为完整核糖体的沉降系数降低，未组装的核糖体亚单位水平增加，与有丝分裂相关联的特定蛋白(MLP)水平改变。这伴随着线粒体呼吸受损，并导致ETC复合体水平和活性的有害变化。这些拟议的研究旨在调查一种假说，即在酒精动物中看到的肝有丝分裂体功能障碍是由于特定MRP的表达缺陷引起的有丝分裂体组装的损害。具体地说，我们将(I)确定对亚单位-亚单位关联至关重要的MRP-蛋白质和MRP-rRNA关联；(Ii)确定对乙醇引起的减少特别敏感的MRP；(Iii)确定可能参与MRP表达控制的转录因子，尤其是乙醇响应的MRP基因。希望这些研究将有助于阐明乙醇导致线粒体蛋白质合成障碍的分子机制(S)，并有助于进一步了解酒精性肝病进展的早期阶段。酒精性肝病是严重危害公众健康的疾病。仅在美国，肝硬变就是年轻人和中年人的第七大死亡原因。每年约有10,000至24,000人死于肝硬变，原因可能是饮酒。

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.