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.
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.
| Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen et al. (2018) Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy. Free Radic Biol Med 123:116-124 |
| Gomez, Jose D; Ridgeway, Mark E; Park, Melvin A et al. (2018) Utilizing Ion Mobility to Identify Isobaric Post-Translational Modifications: Resolving Acrolein and Propionyl Lysine Adducts by TIMS Mass Spectrometry. Int J Ion Mobil Spectrom 21:65-69 |
| Harris, Peter S; Gomez, Joe D; Backos, Donald S et al. (2017) Characterizing Sirtuin 3 Deacetylase Affinity for Aldehyde Dehydrogenase 2. Chem Res Toxicol 30:785-793 |
| Wagner, Gregory R; Bhatt, Dhaval P; O'Connell, Thomas M et al. (2017) A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation. Cell Metab 25:823-837.e8 |
| Anderson, Kristin A; Madsen, Andreas S; Olsen, Christian A et al. (2017) Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio. Biochim Biophys Acta Bioenerg 1858:991-998 |
| Heit, Claire; Marshall, Stephanie; Singh, Surrendra et al. (2017) Catalase deletion promotes prediabetic phenotype in mice. Free Radic Biol Med 103:48-56 |
| Assiri, Mohammed A; Roy, Samantha R; Harris, Peter S et al. (2017) Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation. Alcohol Clin Exp Res 41:1705-1714 |
| Hershberger, Kathleen A; Martin, Angelical S; Hirschey, Matthew D (2017) Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat Rev Nephrol 13:213-225 |
| Martin, Angelical S; Abraham, Dennis M; Hershberger, Kathleen A et al. (2017) Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. JCI Insight 2: |
| Galligan, James J; Kingsley, Philip J; Wauchope, Orrette R et al. (2017) Quantitative Analysis and Discovery of Lysine and Arginine Modifications. Anal Chem 89:1299-1306 |
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