Increased hypoxia in response to ethanol contributes to hepatotoxicity through mechanisms that are not understood in detail. Mitochondria! 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013395-10
Application #
8018047
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Murray, Gary
Project Start
2002-03-05
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
10
Fiscal Year
2011
Total Cost
$280,374
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Mitchell, Tanecia; Chacko, Balu; Ballinger, Scott W et al. (2013) Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics. Biochem Soc Trans 41:127-33
Reily, Colin; Mitchell, Tanecia; Chacko, Balu K et al. (2013) Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol 1:86-93
Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua (2013) Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med 63:207-21
Cummins, Timothy D; Higdon, Ashlee N; Kramer, Philip A et al. (2013) Utilization of fluorescent probes for the quantification and identification of subcellular proteomes and biological processes regulated by lipid peroxidation products. Free Radic Biol Med 59:56-68
Mitchell, Tanecia; Johnson, Michelle S; Ouyang, Xiaosen et al. (2013) Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(+/Ins2)-derived ?-cells. Am J Physiol Endocrinol Metab 305:E585-99
Kalyanaraman, Balaraman; Darley-Usmar, Victor; Davies, Kelvin J A et al. (2012) Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med 52:1-6
Higdon, Ashlee; Diers, Anne R; Oh, Joo Yeun et al. (2012) Cell signalling by reactive lipid species: new concepts and molecular mechanisms. Biochem J 442:453-64
Darley-Usmar, Victor M; Ball, Lauren E; Chatham, John C (2012) Protein O-linked *-N-acetylglucosamine: a novel effector of cardiomyocyte metabolism and function. J Mol Cell Cardiol 52:538-49
Mitchell, Tanecia; Chacko, Balu K; Darley-Usmar, Victor (2012) Controlling radicals in the powerhouse: development of MitoSOD. Chem Biol 19:1217-8
Higdon, Ashlee N; Landar, Aimee; Barnes, Stephen et al. (2012) The electrophile responsive proteome: integrating proteomics and lipidomics with cellular function. Antioxid Redox Signal 17:1580-9

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