Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury

Naoko Hanawa, Mie Shinohara, Behnam Saberi, William A. Gaarde, Derick Han, Neil Kaplowitz

Research output: Contribution to journalArticle

Abstract

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 H 2O2 release from mitochondria, which preceded JNK activation (maximal at 4 h); 2) treatment of isolated hepatocytes with H 2O2 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.

Original languageEnglish (US)
Pages (from-to)13565-13577
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
StatePublished - May 16 2008
Externally publishedYes

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Mitochondria
Acetaminophen
Liver
Energy Metabolism
Wounds and Injuries
Chemical activation
Respiration
Permeability
Reactive Oxygen Species
Gastroenterology
Cyclosporine
Hepatocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. / Hanawa, Naoko; Shinohara, Mie; Saberi, Behnam; Gaarde, William A.; Han, Derick; Kaplowitz, Neil.

In: Journal of Biological Chemistry, Vol. 283, No. 20, 16.05.2008, p. 13565-13577.

Research output: Contribution to journalArticle

Hanawa, Naoko ; Shinohara, Mie ; Saberi, Behnam ; Gaarde, William A. ; Han, Derick ; Kaplowitz, Neil. / Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 20. pp. 13565-13577.
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AU - Hanawa, Naoko

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AU - Saberi, Behnam

AU - Gaarde, William A.

AU - Han, Derick

AU - Kaplowitz, Neil

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