C-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation.
The c-Jun N-terminal kinase (JNK) pathway enhances graft injury after liver transplantation (LT). We hypothesized that the JNK2 isoform promotes graft injury via the mitochondrial permeability transition (MPT). Livers of C57BL/6J (wild-type, WT) and JNK2 knockout (KO) mice were transplanted into WT recipients after 30 h of cold storage in UW solution. Injury after implantation was assessed by serum ALT, histological necrosis, TUNEL, Caspase 3 activity, 30-day survival, and cytochrome c and 4-hydroxynonenal immunostaining. Multiphoton microscopy after LT monitored mitochondrial membrane potential in vivo. After LT, ALT increased three times more in WT compared to KO (p < 0.05). Necrosis and TUNEL were more than two times greater in WT than KO (p < 0.05). Immunostaining showed a >80% decrease of mitochondrial cytochrome c release in KO compared to WT (p < 0.01). Lipid peroxidation was similarly decreased. Every KO graft but one survived longer than all WT grafts (p < 0.05, Kaplan-Meier). After LT, depolarization of mitochondria occurred in 73% of WT hepatocytes, which decreased to 28% in KO (p < 0.05). In conclusion, donor JNK2 promotes injury after mouse LT via the MPT. MPT inhibition using specific JNK2 inhibitors may be useful in protecting grafts against adverse outcomes from ischemia/reperfusion injury.
Theruvath
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TP
Center for Cell Death, Injury & Regeneration, Department of Pharmaceutical & Biomedical Sciences, University of South Carolina, Charleston, SC, USA.
Czerny
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C
Ramshesh
V K
VK
Zhong
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Z
Chavin
K D
KD
Lemasters
J J
JJ
D000410:Alanine Transaminase / Q000097:blood; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation; D016031:Liver Transplantation / Q000009:adverse effects* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D009336:Necrosis / Q000473:pathology; D010539:Permeability; D011446:Prospective Studies; D011897:Random Allocation; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019737:Transplants / Q000009:adverse effects*
D000447:Aldehydes; D007527:Isoenzymes; D000410:Alanine Transaminase; D048056:Mitogen-Activated Protein Kinase 9; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal