Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion
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Background & aims Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin (MnTMPyP) on oxidatively modified proteins and their functions.Methods The oxidized and/or S-nitrosylated mitochondrial proteins from I/R-injured mouse livers with or without MnTMPyP pretreatment were labeled with biotin-N-maleimide, purified with streptavidin-agarose, and resolved by 2-dimensional gel electrophoresis. The identities of the oxidatively modified proteins were determined using mass spectrometric analysis. Liver histopathology, serum transaminase levels, nitrosative stress markers, and activities of oxidatively modified mitochondrial proteins were measured.Results Comparative 2-dimensional gel analysis revealed markedly increased numbers of oxidized and S-nitrosylated mitochondrial proteins following hepatic I/R injury. Many key mitochondrial enzymes involved in cellular defense, fat metabolism, energy supply, and chaperones were identified as being oxidatively modified proteins. Pretreatment with MnTMPyP attenuated the I/R-induced increased serum transaminase levels, histologic damage, increased inducible nitric oxide synthase expression, and S-nitrosylation and/or nitration of various key mitochondrial proteins. MnTMPyP pretreatment also restored I/R-induced suppressed activities of mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolases, and adenosine triphosphate synthase.Conclusions These results suggest that increased nitrosative stress is critically important in promoting S-nitrosylation and nitration of various mitochondrial proteins, leading to mitochondrial dysfunction with decreased energy supply and increased hepatic injury.
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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 [204]
Similar numbers of oxidatively-modified mitochondrial proteins were identified by mass-spectral analysis in mice with I/R injury and rats exposed to MDMA.
“Similar numbers of oxidatively-modified mitochondrial proteins were also identified by mass-spectral analysis in mice with I/R injury [38] and rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) [39].”
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].”
Based on our results, similar results of mitochondrial dysfunction and tissue injury are expected with other conditions such as I/R injury and LPS treatment, which caused extensive protein nitration.
“Based on our results, we expect similar results of mitochondrial dysfunction and tissue injury with other conditions such as I/R injury [38] and LPS treatment [96], which caused extensive protein nitration.”
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“and inactivation of ALDH2 were also observed after exposure to MDMA [39] or I/R injury [38], resulting in the accumulation of”
BackgroundResultInfluentialSelf-citationAbdelmegeed, M. A., Jang, S., Banerjee, A., Hardwick, J. P., & Song, B.-J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.018 · Cited by 85 · see citing works
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Self-citation
- Authors
- Moon, K., Hood, B. L., Mukhopadhyay, P., Rajesh, M., Abdelmegeed, M. A., Kwon, Y., Conrads, T. P., Veenstra, T. D., Song, B., & Pacher, P.
- Affiliations
- National Institutes of Health (US)
- Science Applications International Corporation (United States) (US)
- National Institute on Alcohol Abuse and Alcoholism (US)
- Corresponding author
- Song, Byoung–Joon
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 135
- Issue
- 4
- Pages
- 1344-1357
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2597302
- OpenAlex
- W2106174458
- Cited by
- 103
- References
- 52
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 10 · 2014: 7 · 2013: 8 · 2012: 10
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- Funders
- National Institutes of Health (n01co12400-79-0-22, Z99‐AA999999)
- National Institute on Alcohol Abuse and Alcoholism (Z01AA000375, Z01AA000036)
- National Cancer Institute (N01-CO-012400)
- Topics
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- hepatic ischemia-reperfusion injury, mitochondrial dysfunction, oxidized proteins, S-nitrosylation, nitration, nitrosative stress, superoxide dismutase mimetic, MnTMPyP, mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolase, ATP synthase, liver injury, energy metabolism
- MeSH terms
- Alanine Transaminase, Animals, Aspartate Aminotransferases, Energy Metabolism, Enzymes, Liver, Male, Metalloporphyrins, Mice, Inbred C57BL, Nitrites, Nitrogen, Oxidation-Reduction, Superoxide Dismutase, Tyrosine, Reperfusion Injury, Oxidative Stress, Sequence Analysis, Protein, Mitochondrial Proteins, Mice, Nitric Oxide Synthase Type II, Tandem Mass Spectrometry
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