Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury.
The mechanism by which c-Jun N-terminal protein kinase (JNK) promotes tissue injury is poorly understood. Thus we aimed at studying the roles of JNK and its phospho-target proteins in mouse models of acute liver injury. Young male mice were exposed to a single dose of CCl4 (50mg/kg, IP) and euthanized at different time points. Liver histology, blood alanine aminotransferase, and other enzyme activities were measured in CCl4-exposed mice without or with the highly-specific JNK inhibitors. Phosphoproteins were purified from control or CCl4-exposed mice and analyzed by differential mass-spectrometry followed by further characterizations of immunoprecipitation and activity measurements. JNK was activated within 1h while liver damage was maximal at 24h post-CCl4 injection. Markedly increased phosphorylation of many mitochondrial proteins was observed between 1 and 8h following CCl4 exposure. Pretreatment with the selective JNK inhibitor SU3327 or the mitochondria-targeted antioxidant mito-TEMPO markedly reduced the levels of p-JNK, mitochondrial phosphoproteins and liver damage in CCl4-exposed mice. Differential proteomic analysis identified many phosphorylated mitochondrial proteins involved in anti-oxidant defense, electron transfer, energy supply, fatty acid oxidation, etc. Aldehyde dehydrogenase, NADH-ubiquinone oxidoreductase, and α-ketoglutarate dehydrogenase were phosphorylated in CCl4-exposed mice but dephosphorylated after SU3327 pretreatment. Consistently, the suppressed activities of these enzymes were restored by SU3327 pretreatment in CCl4-exposed mice. These data provide a novel mechanism by which JNK, rapidly activated by CCl4, promotes mitochondrial dysfunction and acute hepatotoxicity through robust phosphorylation of numerous mitochondrial proteins.
['Jang|Sehwan|S|', 'Yu|Li-Rong|LR|', 'Abdelmegeed|Mohamed A|MA|', 'Gao|Yuan|Y|', 'Banerjee|Atrayee|A|', 'Song|Byoung-Joon|BJ|']
D055371:Acute Lung Injury D000818:Animals D019392:Cytochrome P-450 CYP2E1 D004789:Enzyme Activation D048031:JNK Mitogen-Activated Protein Kinases D008297:Male D057507:Mice, 129 Strain D008822:Mice, Transgenic D008930:Mitochondria, Liver D024101:Mitochondrial Proteins D010766:Phosphorylation D011499:Protein Processing, Post-Translational D051028:bcl-2-Associated X Protein
Acute liver injury JNK Differential proteomics Carbon tetrachloride Mitochondria Protein phosphorylation