Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats
Abstract
Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S-nitrosylated mitochondrial proteins and to use a biotin-N-maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin-N-maleimide-labeled oxidized and/or S-nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S-nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial beta-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion, our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage.
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Chronic and excessive alcohol intake is known to cause liver injury from mild steatosis (AFLD) to more advanced liver disease such as ASH, fibrosis/cirrhosis, hepatic cancer, liver failure, and death.
“Chronic and excessive alcohol intake is known to cause liver injury from mild steatosis (simple fat accumulation in so-called alcoholic fatty liver disease, AFLD) to more advanced liver disease such as inflammation (alcoholic steatohepatitis, ASH), fibrosis/cirrhosis, hepatic cancer, liver failure, and death203–213.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [203]
Mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents.
“In fact, mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents [34], [35].”
If an amino acid serves as the active site or is located near the active site of certain enzymes, oxidative modifications of these amino acids can result in their inactivation, as shown by oxidation and/or S-nitrosylation of Cys residues including the active site Cys in ALDH2 and thiolase in binge alcohol-exposed rodents.
“If one of these amino acids serves as the active site or is located near the active site of certain enzymes, it is highly likely that oxidative modifications of these amino acids can result in their inactivation, as shown by the oxidation and/or S-nitrosylation of Cys residues including the active site Cys in the mitochondrial aldehyde dehydrogenase (ALDH2) [34] and 3-keto-acyl CoA-thiolase (thiol”
Similar modifications and inactivation of active site Cys residues in thiolase and possibly other enzymes in the β-oxidation pathway of fatty acids are likely to lead to fat accumulation observed in alcohol-exposed rodents, MDMA-exposed rats and mouse liver following I/R injury.
“Similar modifications and inactivation of active site Cys residues in thiolase and possibly other enzymes in the β-oxidation pathway of fatty acids are likely to lead to fat accumulation observed in alcohol-exposed rodents [34], in MDMA-exposed rats [39] as well as in mouse liver following I/R injury [38].”
These phenomena could explain the decreased levels of ALDH2 activity in alcoholic individuals.
“In fact, these phenomena could explain the decreased levels of ALDH2 activity in alcoholic individuals, as discussed [34], [42].”
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“exposed rats was fully restored by DDT treatment [34].”
BackgroundInfluentialSelf-citationMoon, K., Hood, B. L., Mukhopadhyay, P., Rajesh, M., Abdelmegeed, M. A., Kwon, Y., Conrads, T. P., Veenstra, T. D., Song, B., & Pacher, P. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.048 · Cited by 103 · see citing works
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Self-citation
- Authors
- Moon, K.-H., Hood, B. L., Kim, B.-J., Hardwick, J. P., Conrads, T. P., Veenstra, T. D., & Song, B. J.
- Affiliations
- National Institutes of Health (US)
- Science Applications International Corporation (United States) (US)
- Northeast Ohio Medical University (US)
- Corresponding author
- Song, Byoung J.
- Venue
- Hepatology
- Published
- 2006-11
- Volume
- 44
- Issue
- 5
- Pages
- 1218-1230
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2095884290
- Cited by
- 120
- References
- 50
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 4
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- Funders
- National Institutes of Health (n01co12400-79-0-22)
- National Cancer Institute (N01CO12400)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- alcoholic fatty liver, S-nitrosylation, oxidative stress, nitrosative stress, mitochondrial dysfunction, chronic ethanol exposure, ALDH2, ATP synthase, 3-ketoacyl-CoA thiolase, fatty acid beta-oxidation, CYP2E1, inducible nitric oxide synthase, nitric oxide, molecular chaperones, mitochondrial electron transport chain, ion transport, hepatic lipid accumulation
- MeSH terms
- Ethanol, Animals, Central Nervous System Depressants, Cysteine, Fatty Liver, Alcoholic, Isoenzymes, Male, Maleimides, Mitochondria, Liver, Nitrites, Oxidation-Reduction, Nitrosation, Rats, Sprague-Dawley, Oxidative Stress, Nitric Oxide Synthase, Cytochrome P-450 CYP2E1, Sequence Analysis, Protein, Mitochondrial Proteins, Rats
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