4-hydroxynonenal inhibits SIRT3 via thiol-specific modification
Open accessAbstract
4-Hydroxynonenal (4-HNE) is an endogenous product of lipid peroxidation known to play a role in cellular signaling through protein modification and is a major precursor for protein carbonyl adducts found in alcoholic liver disease (ALD). In the present study, a greater than 2-fold increase in protein carbonylation of sirtuin 3 (SIRT3), a mitochondrial class III histone deacetylase, is reported in liver mitochondrial extracts of ethanol-consuming mice. The consequence of this in vivo carbonylation on SIRT3 deacetylase activity is unknown. Interestingly, mitochondrial protein hyperacetylation was observed in a time-dependent increase in a model of chronic ethanol consumption; however, the underlying mechanisms for this remain unknown. Tandem mass spectrometry was used to identify and characterize the in vitro covalent modification of rSIRT3 by 4-HNE at Cys(280), a critical zinc-binding residue, and the resulting inhibition of rSIRT3 activity via pathophysiologically relevant concentrations of 4-HNE. Computational-based molecular modeling simulations indicate that 4-HNE modification alters the conformation of the zinc-binding domain inducing minor changes within the active site, resulting in the allosteric inhibition of SIRT3 activity. These conformational data are supported by the calculated binding energies derived from molecular docking studies suggesting the substrate peptide of acetyl-CoA synthetase 2 (AceCS2-K(ac)) and display a greater affinity for native SIRT3 as compared with the 4-HNE adducted protein. The results of this study characterize altered mitochondrial protein acetylation in a mouse model of chronic ethanol ingestion and thiol-specific allosteric inhibition of rSIRT3 resulting from 4-HNE adduction.
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The active site Cys301 of ALDH2 and Cys280 in the critical Zn binding site of sirtuin 3 were covalently modified with 4-HNE, leading to their inactivation.
“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”
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“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”
BackgroundFritz, K. S., Galligan, J. J., Hirschey, M. D., Verdin, E., & Petersen, D. R. (2012) · Journal of Proteome Research · doi:10.1021/pr2008384 · Cited by 121 · see citing works
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Protein Carbonylation in a Murine Model for Early Alcoholic Liver Disease
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Ronis, M. J. J., Mercer, K. E., Gannon, B., Engi, B., Zimniak, P., Shearn, C. T., Orlicky, D. J., Albano, E., Badger, T. M., & Petersen, D. R. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00154.2014 · Cited by 27 · see citing works
Self-citation
- Authors
- Fritz, K. S., Galligan, J. J., Smathers, R. L., Roede, J. R., Shearn, C. T., Reigan, P., & Petersen, D. R.
- Affiliations
- University of Colorado Denver (US)
- Emory University (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Petersen, Dennis R.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-04-14
- Volume
- 24
- Issue
- 5
- Pages
- 651-662
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- PMC
- PMC3113719
- OpenAlex
- W2001296325
- Cited by
- 127
- References
- 54
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 8 · 2018: 7 · 2017: 7 · 2016: 11 · 2015: 16 · 2014: 12 · 2013: 13 · 2012: 15
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f31aa018606-01)
- National Institute on Alcohol Abuse and Alcoholism (F31 AA018606, F31AA018606-01, F31AA18898-01, F31AA018898, R37AA009300)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074487)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- 4-hydroxynonenal, SIRT3, protein carbonylation, lipid peroxidation, allosteric inhibition, mitochondrial protein acetylation, chronic alcohol consumption, alcoholic liver disease, zinc-binding domain, acetyl-CoA synthetase 2, histone deacetylase, molecular docking, molecular modeling
- MeSH terms
- Acetylation, Ethanol, Aldehydes, Amino Acid Sequence, Animals, Humans, Mice, Inbred C57BL, Mitochondria, Liver, Models, Molecular, Molecular Sequence Data, NAD, Sulfhydryl Compounds, Lipid Peroxidation, Sequence Alignment, Protein Carbonylation, Mice, Sirtuin 3
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