Mitochondrial permeability transition in liver ischemia and reperfusion: role of c-Jun N-terminal kinase 2.
The mitochondrial permeability transition (MPT) mediates hepatic necrosis after ischemia and reperfusion (I/R). Here, we studied the role of c-Jun N-terminal kinase 2 (JNK2) in MPT-induced liver injury. Wildtype (WT) and JNK2 knockout (KO) mice underwent 70% liver ischemia for 1 hr followed by reperfusion for 8 hr, after which hepatocyte injury and animal survival was assessed. Compared with WT, JNK2 KO mice had 38% less alanine transaminase release and 39% less necrosis by histology. Survival out to 14 days was also greater in JNK2 KO mice (57% vs. 11%), and overall Kaplan-Meier survival was improved. No difference in apoptosis was observed. Intravital multiphoton microscopy of potential-indicating rhodamine 123 after reperfusion revealed depolarized mitochondria in 82% of WT hepatocytes, which decreased to 43% in JNK2 KO hepatocytes. In conclusion, JNK2 contributes to hepatocellular injury and death after I/R in association with increased mitochondrial dysfunction via the MPT.
Theruvath
Tom P
TP
Center for Cell Death, Injury and Regeneration, Department of Pharmaceutical and Biomedical Sciences, Charleston, SC, USA.
Snoddy
Mark C
MC
Zhong
Zhi
Z
Lemasters
John J
JJ
D000818:Animals; D017209:Apoptosis; D007425:Intracellular Membranes / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000378:metabolism*; D010539:Permeability; D015427:Reperfusion Injury / Q000503:physiopathology*
D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases