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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015172-03
Application #
7098820
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Guo, Qingbin
Project Start
2004-09-15
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$247,788
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K et al. (2016) The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease. Redox Biol 9:188-197
Theis, Whitney S; Andringa, Kelly K; Millender-Swain, Telisha et al. (2014) Ozone inhalation modifies the rat liver proteome. Redox Biol 2:52-60
Betancourt, Angela M; King, Adrienne L; Fetterman, Jessica L et al. (2014) Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice. Biochem J 461:223-32
King, Adrienne L; Swain, Telisha M; Mao, Zhengkuan et al. (2014) Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice. Am J Physiol Gastrointest Liver Physiol 306:G265-77
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
Kharbanda, Kusum K; Todero, Sandra L; King, Adrienne L et al. (2012) Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome. Int J Hepatol 2012:962183
Eccleston, Heather B; Andringa, Kelly K; Betancourt, Angela M et al. (2011) Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. Antioxid Redox Signal 15:447-59
King, Adrienne L; Swain, Telisha M; Dickinson, Dale A et al. (2010) Chronic ethanol consumption enhances sensitivity to Ca(2+)-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver. Am J Physiol Gastrointest Liver Physiol 299:G954-66
Andringa, Kelly K; King, Adrienne L; Eccleston, Heather B et al. (2010) Analysis of the liver mitochondrial proteome in response to ethanol and S-adenosylmethionine treatments: novel molecular targets of disease and hepatoprotection. Am J Physiol Gastrointest Liver Physiol 298:G732-45
Andringa, Kelly K; Bailey, Shannon M (2010) Detection of protein thiols in mitochondrial oxidative phosphorylation complexes and associated proteins. Methods Enzymol 474:83-108

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