Redox Modification of Thiols in Alcohol Hepatotoxicity

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DESCRIPTION (provided by applicant): Chronic alcohol consumption causes liver damage by a complex process involving oxidative and nitrosative stress, hypoxia, upregulation of proinflammatory cytokines, and defects in energy metabolism. As both a source for the formation and target of modifications mediated by reactive oxygen and nitrogen species (ROS/RNS), the mitochondrion is recognized as a site critical in cellular stress responses. Emerging evidence indicates that ROS/RNS-mediated stress disrupts mitochondrial function. Changes in the thiol redox status of mitochondrial proteins is proposed to be important in regulating several mitochondrial functions including respiration, cytokine signaling, the mitochondria permeability transition, and apoptosis. The similarity between the effects of chronic alcohol consumption and changes in mitochondrial protein thiol status strongly supports a mechanistic link for the oxidation of protein thiols in mitochondria contributing to alcohol-induced cell death. Recent studies have suggested that the therapeutic effects of S-adenosylmethionine (SAM) in treating alcohol-induced liver injury are mediated though mitochondrial pathways. In this proposal it is hypothesized that SAM administration during chronic alcohol consumption will preserve hepatic mitochondrial function in response to increases in ROS/RNS through thiol-dependent mechanisms. Thus, the overall goal of this project is to identify mechanisms that link SAM-mediated protection to the effects of ROS/RNS on mitochondrial function in response to chronic alcohol. These concepts will be tested by the pursuit of the following Specific Aims in a well characterized rat model of chronic alcohol consumption which produces mitochondrial dysfunction in liver: (1) Determine the effects of SAM on chronic alcohol-mediated modulation of mitochondrial protein thiol redox status. (2) Determine the effect of SAM supplementation on chronic alcohol-induced changes in NO-dependent control of mitochondrial respiration. (3) Characterize the influence of SAM administration on alcohol-induced mtDNA damage, mitochondrial protein synthesis defects, and the regulatory function of prohibitin/BAP37 in respiratory complex assembly. These studies will generate novel information on the mechanisms of redox regulation of mitochondrial protein thiols in alcohol toxicity. New information on the molecular targets of SAM will also be achieved, which will enable the design of effective therapeutic strategies to treat liver diseases.