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Grant Abstract

Grant Number: 5R21AA014151-01
PI Name: Alan Cahill
Project Title: Mitochondrial rRNA Methylation: Effects of ethanol/SAMe

Abstract: 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.

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