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Updated: May 31, 2026
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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
Published on: February 27, 2016
SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity
Zhongping Lu1, Mohammed Bourdi, Jian H Li
1Center for Molecular Medicine, NHLBI, National Institutes of Health, Building 10-CRC, Room 5-3150, 10 Center Drive, Bethesda, Maryland 20892, USA.
EMBO Reports
|July 2, 2011
Summary
Fasting worsens acetaminophen liver injury by promoting protein deacetylation. Deacetylation increases toxic metabolite binding to mitochondrial proteins, enhancing liver damage.
Area of Science:
- Biochemistry
- Hepatology
- Mitochondrial Biology
Background:
- Acetaminophen (paracetamol) overdose causes liver failure via reactive metabolites binding to mitochondrial proteins.
- Fasting exacerbates acetaminophen-induced liver injury.
- Fasting is known to promote SIRT3-mediated deacetylation of mitochondrial proteins.
Purpose of the Study:
- To investigate if protein deacetylation predisposes mice to acetaminophen's toxic metabolite-mediated mitochondrial disruption.
- To explore the role of SIRT3 in acetaminophen hepatotoxicity.
Main Methods:
- Utilized SIRT3 knockout (SIRT3-/-) mice to assess acetaminophen hepatotoxicity.
- Identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as a direct SIRT3 substrate.
- Examined the impact of ALDH2 deacetylation on acetaminophen toxic metabolite binding and enzyme activity.
Main Results:
- SIRT3 knockout mice were protected from acetaminophen-induced liver injury.
- Deacetylation of ALDH2 by SIRT3 increased the binding of toxic acetaminophen metabolites.
- ALDH2 enzyme inactivation was enhanced by deacetylation, contributing to liver damage.
Conclusions:
- Protein deacetylation, specifically by SIRT3, enhances xenobiotic liver injury.
- Deacetylation modulates the binding of toxic metabolites to critical mitochondrial proteins like ALDH2.
- Targeting SIRT3-mediated deacetylation may offer a therapeutic strategy against acetaminophen-induced liver failure.
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