Mitochondrial Acetylome
Analysis in a Mouse Model
of Alcohol-Induced Liver Injury Utilizing SIRT3 Knockout Mice
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Abstract
Mitochondrial protein hyperacetylation is a known consequence
of
sustained ethanol consumption and has been proposed to play a role
in the pathogenesis of alcoholic liver disease (ALD). The mechanisms
underlying this altered acetylome, however, remain unknown. The mitochondrial
deacetylase sirtuin 3 (SIRT3) is reported to be the major regulator
of mitochondrial protein deacetylation and remains a central focus
for studies on protein acetylation. To investigate the mechanisms
underlying ethanol-induced mitochondrial acetylation, we employed
a model for ALD in both wild-type (WT) and SIRT3 knockout (KO) mice
using a proteomics and bioinformatics approach. Here, WT and SIRT3
KO groups were compared in a mouse model of chronic ethanol consumption,
revealing pathways relevant to ALD, including lipid and fatty acid
metabolism, antioxidant response, amino acid biosynthesis and the
electron-transport chain, each displaying proteins with altered acetylation.
Interestingly, protein hyperacetylation resulting from ethanol consumption
and SIRT3 ablation suggests ethanol-induced hyperacetylation targets
numerous biological processes within the mitochondria, the majority
of which are known to be acetylated through SIRT3-dependent mechanisms.
These findings reveal overall increases in 91 mitochondrial targets
for protein acetylation, identifying numerous critical metabolic and
antioxidant pathways associated with ALD, suggesting an important
role for mitochondrial protein acetylation in the pathogenesis of
ALD