Chronic Ethanol Feeding and the Mitochondrial Ribosomal Proteins

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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.