Mitochondrial rRNA Methylation: Effects of ethanol/SAMe

线粒体 rRNA 甲基化：乙醇/SAMe 的影响

• 批准号: 6593557
• 负责人: ALAN CAHILL
• 金额: $ 15.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593557
• 关键词: RNA methylation; S adenosylmethionine; alcoholic beverage consumption; bioenergetics; ethanol; laboratory rat; mitochondria; mitochondrial DNA; molecular assembly /self assembly; molecular pathology; ribosomal RNA; ribosomes; toxicology

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.

描述（由申请人提供）：提议研究以下假设：慢性乙醇喂养会导致肝S-腺苷-l-甲硫氨酸（ADOMET）的水平降低，并且这种缺乏会导致线粒体核糖体组装和抑郁蛋白合成。已发表的数据表明，乙醇对肝脏中的氧化磷酸化具有明显的作用。乙醇的消耗导致编码的必需多肽水平降低：仅由线粒体基因组 - 用于电子传输链（ETC）配合物的组装中。 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在酒精性肝病（ALD）进展过程中，参与能量代谢损害涉及的一种潜在的动力学之一。线粒体核糖体的组装需要核编码蛋白和线粒体 编码的核糖体RNA（rRNA）颗粒。它还需要rRNA中少量核苷酸的位点特异性甲基化，这是利用ADOMET的过程。已发表的数据表明，慢性乙醇消耗会导致细胞ADOMET的耗竭，这可能对核糖体组装产生重大影响。此外，我们小组的研究表明，慢性乙醇对2岁的雄性大鼠持续14天导致电子传输链复合物I的活性显着降低，并且可以通过与ADOMET的同时治疗来改善这一点。拟议的研究将（a）研究rRNA甲基化对核糖体组装和功能的重要性； （b）研究慢性乙醇喂养对rRNA甲基化的影响； （c）线粒体rRNA甲基转移酶的活性。也将研究ADOMET对（B）和（C）中研究的影响。希望这些分析能够为线粒体蛋白翻译I的作用提供独特的见解。