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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017773-05
Application #
8319655
Study Section
Special Emphasis Panel (ZAA1-JJ (17))
Program Officer
Murray, Gary
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$411,956
Indirect Cost
$145,318
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Eisner, Verónica; Lenaers, Guy; Hajnóczky, György (2014) Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J Cell Biol 205:179-95
Weaver, David; Eisner, Verónica; Liu, Xingguo et al. (2014) Distribution and apoptotic function of outer membrane proteins depend on mitochondrial fusion. Mol Cell 54:870-8
Twig, Gilad; Liu, Xingguo; Liesa, Marc et al. (2010) Biophysical properties of mitochondrial fusion events in pancreatic beta-cells and cardiac cells unravel potential control mechanisms of its selectivity. Am J Physiol Cell Physiol 299:C477-87
Liu, Xingguo; Weaver, David; Shirihai, Orian et al. (2009) Mitochondrial 'kiss-and-run': interplay between mitochondrial motility and fusion-fission dynamics. EMBO J 28:3074-89