Ethanol Hepatotoxicity and NO-Dependent Mitochondrial Dysfunction

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DESCRIPTION (provided by applicant): Increased hypoxia in response to ethanol contributes to hepatotoxicity through mechanisms that are not understood in detail. Mitochondrial dysfunction and the associated formation of reactive oxygen and nitrogen species (ROS/RNS) appear to be a consequence of alcohol exposure in the liver. We hypothesized that ethanol-dependent hypoxia involved a contribution from the nitric oxide (NO) interaction with the mitochondrial respiratory chain, and this has been supported by studies undertaken in the previous funding period. In this competing renewal, we build upon these findings that demonstrate a) enhanced sensitivity to the NO-dependent inhibition of mitochondrial respiration occurs early on exposure to alcohol b) this response is ablated in mice lacking the inducible NO synthase isoform c) these changes are associated with changes in the mitochondrial proteome and oxidative modification of proteins and mitochondrial DNA. These data have led to the hypothesis that alcohol hepatotoxicity is exacerbated through increased mitochondrial dysfunction and these effects will be ameliorated by mitochondrially targeted antioxidants. This concept will be tested by pursuit of the following Specific Aims: 1. Determine the effect of mitochondrially targeted antioxidants (MTA) on the development of alcohol-dependent hepatoxicity and hypoxia. 2: Determine the effects of MTA on the chronic alcohol-dependent changes in activity of mitochondrial proteins, sensitivity to inhibition of the respiratory chain by NO and damage to mtDNA. 3: Determine the effects of MTA on the ethanol dependent modifications of the mitochondrial proteome. This project will contribute to public health through defining the mechanisms that lead to the liver damage that occurs in response to chronic alcoholism. In addition, the possibility of using a new class of drugs directed to the parts of the cell that produce energy to reverse or prevent these toxic effects of alcohol will be tested.