Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation

Alcohol Clin Exp Res. 2017 Oct;41(10):1705-1714. doi: 10.1111/acer.13473. Epub 2017 Sep 14.


Background: Chronic ethanol (EtOH) consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of EtOH metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how EtOH consumption leads to ALD. Recent studies suggest that EtOH metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins.

Methods: To elucidate mechanisms of EtOH-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of EtOH consumption. Our experimental approach includes immunoblotting immunohistochemistry (IHC), activity assays, mass spectrometry, and in silico modeling.

Results: We found that EtOH metabolism significantly increased the acetylation of SOD2 at 2 functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. IHC analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main EtOH-metabolizing region of the liver.

Conclusions: Overall, the findings presented in this study support a role for EtOH-induced lysine acetylation as an adverse posttranslational modification within the mitochondria that directly impacts SOD2 charge state and activity. Last, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic EtOH metabolism.

Keywords: Alcoholic Liver Disease; Lysine Acetylation; Oxidative Stress; Sirtuin; Superoxide Dismutase.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Ethanol / administration & dosage
  • Ethanol / metabolism*
  • Ethanol / toxicity*
  • Liver / drug effects
  • Liver / metabolism*
  • Lysine / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Superoxide Dismutase / antagonists & inhibitors
  • Superoxide Dismutase / metabolism*


  • Ethanol
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Lysine