Quantifying Competition among Mitochondrial Protein Acylation Events Induced by Ethanol Metabolism

J Proteome Res. 2019 Apr 5;18(4):1513-1531. doi: 10.1021/acs.jproteome.8b00800. Epub 2019 Jan 31.


Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways, and recent reports demonstrate that alcohol-induced protein acylation negatively impacts these processes. To identify regulatory mechanisms attributed to alcohol-induced protein post-translational modifications, we employed a model of alcohol consumption within the context of wild type (WT), sirtuin 3 knockout (SIRT3 KO), and sirtuin 5 knockout (SIRT5 KO) mice to manipulate hepatic mitochondrial protein acylation. Mitochondrial fractions were examined by label-free quantitative HPLC-MS/MS to reveal competition between lysine acetylation and succinylation. A class of proteins defined as "differential acyl switching proteins" demonstrate select sensitivity to alcohol-induced protein acylation. A number of these proteins reveal saturated lysine-site occupancy, suggesting a significant level of differential stoichiometry in the setting of ethanol consumption. We hypothesize that ethanol downregulates numerous mitochondrial metabolic pathways through differential acyl switching proteins. Data are available via ProteomeXchange with identifier PXD012089.

Keywords: acetylation; alcoholic liver disease; mass spectrometry; mitochondria; proteomics; sirtuins; succinylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acylation / drug effects*
  • Animals
  • Ethanol / pharmacology*
  • Liver Diseases, Alcoholic / metabolism
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Mice
  • Mice, Knockout
  • Mitochondria* / drug effects
  • Mitochondria* / metabolism
  • Proteome* / chemistry
  • Proteome* / drug effects
  • Proteome* / metabolism
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism
  • Sirtuins / genetics
  • Sirtuins / metabolism


  • Proteome
  • SIRT5 protein, mouse
  • Sirt3 protein, mouse
  • Ethanol
  • Sirtuin 3
  • Sirtuins