Inhibition of hepatic mitochondrial aldehyde dehydrogenase by carbon tetrachloride through JNK-mediated phosphorylation
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The aim of this study was to investigate the mechanism of inhibition of mitochondrial aldehyde dehydrogenase (ALDH2) by carbon tetrachloride (CCl(4)). CCl(4) administration caused marked hepatocyte ballooning and necrosis in the pericentral region. CCl(4) also inhibited hepatic ALDH2 activity in a time-dependent manner without altering the protein level, suggesting ALDH2 inhibition through covalent modifications such as phosphorylation by JNK. To demonstrate phosphorylation, the isoelectric point (pI) of ALDH2 in CCl(4)-exposed rats was compared to that of untreated controls. Immunoblot analysis revealed that immunoreactive ALDH2 bands in CCl(4)-exposed rats were shifted to acidic pI ranges on two-dimensional electrophoresis (2-DE) gels. Incubation with alkaline phosphatase significantly restored the suppressed ALDH2 activity with a concurrent alkaline pI shift of the ALDH2 spots. Both JNK and activated JNK were translocated to mitochondria after CCl(4) exposure. In addition, incubation with catalytically active JNK led to significant inhibition of ALDH2 activity, with an acidic pI shift on 2-DE gels. Furthermore, immunoprecipitation followed by immunoblot analysis with anti-phospho-Ser-Pro antibody revealed phosphorylation of a Ser residue(s) of ALDH2. These results collectively indicate a novel underlying mechanism by which CCl(4) exposure activates JNK, which translocates to mitochondria and phosphorylates ALDH2, contributing to inhibition of ALDH2 activity accompanied by decreased cellular defense capacity and increased lipid peroxidation.
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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 [206]
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References 53 · Cited by 37
- Authors
- Moon, K.-H., Lee, Y.-M., & Song, B.-J.
- Affiliations
- National Institute on Alcohol Abuse and Alcoholism (US)
- Corresponding author
- Song, Byoung-Joon
- ORCID
- Song, Byoung-Joon
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 48
- Issue
- 3
- Pages
- 391-398
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2831234
- OpenAlex
- W2045166141
- Cited by
- 37
- References
- 53
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 4
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99‐AA999999)
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000036)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- mitochondrial aldehyde dehydrogenase, ALDH2, carbon tetrachloride, JNK, JNK phosphorylation, hepatotoxicity, liver necrosis, mitochondrial translocation, isoelectric point shift, serine phosphorylation, lipid peroxidation
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Aldehyde Dehydrogenase, Animals, Carbon Tetrachloride, Male, Mitochondria, Liver, Phosphorylation, Immunoblotting, Rats, Sprague-Dawley, Oxidative Stress, Protein Transport, Mitochondrial Proteins, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Rats
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