Mitochondrial Dynamics in Alcohol-induced Tissue Injury

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DESCRIPTION (provided by applicant): Chronic alcohol abuse is associated with diseases of many organs, but the pathogenesis of these conditions still remains obscure. Studies on animal models have demonstrated that chronic ethanol feeding causes structural and functional derangements of mitochondria. Impairments of mitochondrial bioenergetics and the apoptosis-regulating function of mitochondria are considered to be central for the increased cell death in both alcoholic heart and liver disease. Emerging research indicates the interdependence between the factors that regulate mitochondrial morphology and function. Altered expression or mutation of the mitochondrial fusion- fission or motor proteins leads to cell/tissue injury. Our studies provide evidence that chronic ethanol exposure alters the mitochondrial morphology and fusion-fission dynamics. Our hypothesis is that the changes in mitochondrial morphology are crucial events in determining complex cellular and tissue responses to ethanol contributing to tissue injury. The research plan integrates genetics, advanced imaging and biochemistry approaches to unravel mechanisms, regulation and consequences of mitochondrial shape changes during ethanol-induced tissue injury. We have developed an array of live cell imaging approaches to visualize and quantitate both mitochondrial fusion-fission and motility, a toolkit that enables us to uncover the mechanisms, the regulation and impairment of mitochondrial dynamics upon alcohol exposure. The studies will focus on the tissue injury in heart and liver, where cell function relies on a high capacity of mitochondrial metabolism that can be regulated on demand. The experimental models will span the range from cell lines, through primary cultured cells to the intact organ. The experiments are organized into three aims as follows: (1) To determine the effects of chronic alcohol feeding on mitochondrial dynamics and analyze the underlying mechanisms; (2) To establish the relationship between mitochondrial bioenergetics and fusion-fission dynamics in control and alcohol-exposed tissue; (3) To determine whether the alterations in mitochondrial morphology and dynamics contribute to alcohol-induced cell injury. Understanding the role of mitochondrial dynamics in the chronic alcohol abuse-induced tissue injury will afford insights into the pathogenesis of alcoholic liver disease and cardiomyopathy and may open new avenues for developing diagnostic, prognostic and therapeutic tools. Narrative: Chronic alcoholism is associated with mitochondrial dysfunction and changes in mitochondrial morphology in multiple tissues. Mitochondrial dynamics is envisioned as a target of the alcohol's effect, which underlies changes in mitochondrial morphology which, in turn, lead to mitochondrial dysfunction. Recent progress in the study of mitochondrial structure and function in live cells will enable us to establish the mechanisms and significance of mitochondrial dynamics in the alcoholic liver and cardiac muscle injury.