C-Jun N-Terminal Kinase 2 Promotes Graft Injury via the Mitochondrial Permeability Transition After Mouse Liver Transplantation
Year: 2008
Type: article
Abstract: 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.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
Awards: G129792569, Mechanisms of I/R Injury to Hepatocytes, EXTRAMURAL RESEARCH FACILITIEIS CONSTRUCTION, Liver Preservation for Transplantation, G2108293184, G2598401476, G2686054926, G2956850820, G30753934, G4770008361, G5236184679, G6182624214, G6704308266, G6991517325, G7482654668, LIVER PRESERVATION FOR TRANSPLANTATION, G8013564434, Transplantation of Reduced-Size Fatty Livers, G9000023072, G9000305793
OpenAlex ID: W2016183531