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Role of JNK-Mediated Phosphorylation in Mitochondrial Dysfunction and Liver Injury

Tuesday, October 09, 2012 — Poster Session I

1:00 p.m. – 3:00 p.m

Natcher Conference Center, Building 45



* FARE Award Winner


  • S. Jang
  • Y. Gao
  • M.A. Abdelmegeed
  • A. Banerjee
  • L.L. Yu
  • B.J. Song


Despite the well-established role of JNK in cell death signaling, the target proteins of JNK and their functional implications are poorly understood. Thus we aimed to study the role of JNK and its target proteins in CCl4-mediated acute liver damage. JNK was activated as early as 1 h after CCl4 treatment, while liver damage assessed by histology and ALT levels was maximal at 24 h. Phosphorylation of many mitochondrial proteins were observed at 1-8 h in CCl4-exposed mice. Pretreatment with a JNK inhibitor SU3327 significantly reduced CCl4-mediated hepatotoxicity with marked reduction of phospho-proteins in CCl4-exposed mice, suggesting a causal relationship between phosphorylation and liver damage. Mass spectral analysis of purified phosphorylated proteins revealed that more than 100 mitochondrial proteins including aldehyde dehydrogenase, NADH-ubiquinone oxidoreductase, α-ketoglutarate dehydrogenase were phosphorylated in CCl4-exposed mice. Immunoprecipitation followed by immunoblot with the anti-phospho-Ser-Pro antibody showed that these proteins were markedly phosphorylated in CCl4-exposed mice but SU3327 pretreatment prevented phosphorylation in CCl4-exposed mice. In addition, the suppressed activities of these enzymes were significantly restored by SU3327 pretreatment. These data demonstrate for the first time an important role of JNK-mediated protein phosphorylation in CCl4-induced mitochondrial dysfunction and hepatotoxicity.

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