Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury
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Previously, we demonstrated JNK plays a central role in acetaminophen (APAP)-induced liver injury (Gunawan, B. K., Liu, Z. X., Han, D., Hanawa, N., Gaarde, W. A., and Kaplowitz, N. (2006) Gastroenterology 131, 165-178). In this study, we examine the mechanism involved in activating JNK and explore the downstream targets of JNK important in promoting APAP-induced liver injury in vivo. JNK inhibitor (SP600125) was observed to significantly protect against APAP-induced liver injury. Increased mitochondria-derived reactive oxygen species were implicated in APAP-induced JNK activation based on the following: 1) mitochondrial GSH depletion (maximal at 2 h) caused increased H2O2 release from mitochondria, which preceded JNK activation (maximal at 4 h); 2) treatment of isolated hepatocytes with H2O2 or inhibitors (e.g. antimycin) that cause increased H2O2 release from mitochondria-activated JNK. An important downstream target of JNK following activation was mitochondria based on the following: 1) JNK translocated to mitochondria following activation; 2) JNK inhibitor treatment partially protected against a decline in mitochondria respiration caused by APAP treatment; and 3) addition of purified active JNK to mitochondria isolated from mice treated with APAP plus JNK inhibitor (mitochondria with severe GSH depletion, covalent binding) directly inhibited respiration. Cyclosporin A blocked the inhibitory effect of JNK on mitochondria respiration, suggesting JNK was directly inducing mitochondrial permeability transition in isolated mitochondria from mice treated with APAP plus JNK inhibitor. Addition of JNK to mitochondria isolated from control mice did not affect respiration. Our results suggests that APAP-induced liver injury involves JNK activation, due to increased reactive oxygen species generated by GSH-depleted mitochondria, and translocation of activated JNK to mitochondria where JNK induces mitochondrial permeability transition and inhibits mitochondria bioenergetics.
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Activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP.
“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115], [116], [130], [131].”
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“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115,116,130,131].”
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- Authors
- Hanawa, N., Shinohara, M., Saberi, B., Gaarde, W. A., Han, D., & Kaplowitz, N.
- Affiliations
- University of Southern California (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Kaplowitz, Neil
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 283
- Issue
- 20
- Pages
- 13565-13577
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2376214
- OpenAlex
- W2056309362
- Cited by
- 527
- References
- 60
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 28 · 2023: 33 · 2022: 31 · 2021: 32 · 2020: 44 · 2019: 24 · 2018: 34 · 2017: 36 · 2016: 35 · 2015: 40 · 2014: 35 · 2013: 28 · 2012: 33
- FWCI
- 21.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK067215, DK48522, DK067215, P30DK048522)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- JNK, acetaminophen hepatotoxicity, mitochondrial translocation, mitochondrial permeability transition, mitochondrial respiration, reactive oxygen species, glutathione depletion, hepatotoxicity, SP600125, cyclosporine, mitochondrial bioenergetics, hepatocytes
- MeSH terms
- Acetaminophen, Animals, Anthracenes, Energy Metabolism, Enzyme Inhibitors, Hydrogen Peroxide, Liver, Mitochondria, Mitochondria, Liver, Models, Biological, Oxygen Consumption, Analgesics, Non-Narcotic, Protein Transport, MAP Kinase Kinase 4, Mice
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