Mitochondrial rRNA Methylation: Effects of ethanol/SAMe

描述（由申请人提供）：建议研究慢性乙醇喂养导致肝s -腺苷- l -蛋氨酸（Adomet）水平降低的假设，这种缺乏导致线粒体核糖体组装受损和蛋白质合成抑制。已发表的数据表明，乙醇对肝脏的氧化磷酸化有明显的影响。乙醇消耗导致线粒体基因组专门编码的必要多肽水平下降，这些多肽用于电子传递链（ETC）复合物的组装。因此，它们的活性被抑制，ATP的产生减少，对这一现象的机制的研究揭示了乙醇引起的完全功能的线粒体核糖体（线粒体核糖体）数量的减少，以及它们在分离时解离的增加趋势。这表明，在线粒体多肽翻译水平上，乙醇介导的作用可能是酒精性肝病（ALD）进展过程中能量代谢受损的潜在机制之一。线粒体核糖体的组装需要核编码蛋白和线粒体

DESCRIPTION (provided by applicant): It is proposed to investigate the hypothesis that chronic ethanol feeding results in decreased levels of hepatic S-adenosy-L-methionine (Adomet) and that this deficiency results in impaired mitochondrial ribosome assembly and depressed protein synthesis. Published data has demonstrated that ethanol has a pronounced effect upon oxidative phosphorylation in the liver. Ethanol consumption results in decreased levels of essential polypeptides encoded for: exclusively by the mitochondrial genome-that are utilized in the assembly of electron transport chain (ETC) complexes. As a consequence, their activities are depressed and ATP production decreases, investigations is to the mechanism(s) responsible for the phenomenon revealed an ethanol-elicited decrease in the number of fully functioning mitochondrial ribosomes (mitoribosomes) along with an increased tendency for them to dissociate upon isolation, This suggests that iethanol-mediated effects at the level of mitochondrial polypeptide translation may be one of the underlying imechanisms involved in the impairment of energy metabolism seen during the progression of alcoholic liver disease (ALD). Assembly of mitochondrial ribosomes requires nuclear encoded proteins and mitochondriaUy encoded ribosomal RNA (rRNA) particles. It also requires site-specific methylation of a small number of nucleotides within the rRNA, a process that utilizes Adomet. Published data has shown that chronic ethanol consumption results in depletion of cellular Adomet, which may have significant consequences for ribosome assembly. Further, studies from our group have shown that chronic ethanol-feeding to 2 year old male rats for 14 days results in a significant decrease in the activity of complex I of the electron transport chain and that this can be ameliorated by concomitant treatment with Adomet. The proposed studies will (a) investigate the significance of rRNA methylation upon ribosome assembly and function; (b) investigate the effect of chronic ethanol-feeding upon rRNA methylation; and (c) upon the activity of mitochondrial rRNA methyltransferases. The effect of Adomet feeding upon the studies in (b) and (c) will also be investigated. It is hoped that these analyses will provide a unique insight into the role of mitochondrial protein translation I the progression of ALD.