Chronic ethanol consumption contributes to long-term liver damage, resulting in the initiation and progression of alcoholic liver disease. Unfortunately, the current prognosis for end-stage alcoholic liver disease is poor and often untreatable, largely because the pathogenic mechanisms are not well understood. This research proposal by two early stage investigators puts forward the hypothesis that alcohol metabolism induces changes in mitochondrial protein acetylation, and other newly discovered post-translational modifications including propionylation and succinylation, all resulting in mitochondrial dysfunction. To test this hypothesis, we propose complete proteomic mapping studies, full metabolic characterization, and a series of innovative in vivo mouse physiology experiments with novel murine models, which will lead to a deeper understanding of the role of mitochondria protein acylation during alcohol metabolism. The work performed by our lab will focus specifically on the metabolic characterization, and the in vivo mouse physiology experiments, whereas the work performed by Dr. Fritz will focus on the proteomic mapping studies, as well as in vivo mouse physiology experiments. During the past few years, we have collaborated extensively to map the mitochondrial protein acetylome, and begin to understand the role of acetylation on mitochondrial function during alcohol metabolism. Our preliminary data shows that in addition to changes in acetylation, propionylation and succinylation change in response to alcohol metabolism. Thus, identifying the full repertoire of post- translational modifications and understanding their influence on mitochondrial metabolism are key to understanding the progression of alcoholic liver disease and potential strategies for intervention and treatment.

Public Health Relevance

In the United States, approximately 14 million people meet the diagnostic criteria for alcoholism, two million are estimated to have alcoholic liver disease, and 14,000 die of cirrhotic liver failure annually. This research proposal addresses a novel mechanism for the pathogenesis of alcoholic liver disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Brooks, Pj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
McDonnell, Eoin; Crown, Scott B; Fox, Douglas B et al. (2016) Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation. Cell Rep 17:1463-1472
Heit, Claire; Eriksson, Peter; Thompson, David C et al. (2016) Quantification of Neural Ethanol and Acetaldehyde Using Headspace GC-MS. Alcohol Clin Exp Res 40:1825-31
Madsen, Andreas S; Andersen, Christian; Daoud, Mohammad et al. (2016) Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH. J Biol Chem 291:7128-41
McDonnell, Eoin; Peterson, Brett S; Bomze, Howard M et al. (2015) SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab 26:486-92
Hirschey, Matthew D; Zhao, Yingming (2015) Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation. Mol Cell Proteomics 14:2308-15
Harris, Peter S; Roy, Samantha R; Coughlan, Christina et al. (2015) Chronic ethanol consumption induces mitochondrial protein acetylation and oxidative stress in the kidney. Redox Biol 6:33-40
Wagner, Gregory R; Hirschey, Matthew D (2014) Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol Cell 54:5-16
Anderson, Kristin A; Green, Michelle F; Huynh, Frank K et al. (2014) SnapShot: Mammalian Sirtuins. Cell 159:956-956.e1
Moffat, Cynthia; Bhatia, Lavesh; Nguyen, Teresa et al. (2014) Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver. J Lipid Res 55:2458-70
Huynh, Frank K; Green, Michelle F; Koves, Timothy R et al. (2014) Measurement of fatty acid oxidation rates in animal tissues and cell lines. Methods Enzymol 542:391-405

Showing the most recent 10 out of 17 publications