@article {Sharmamol.112.079863, author = {Manju Sharma and Vidya Gadang and Anja Jaeschke}, title = {Critical Role for Mixed-lineage Kinase 3 in Acetaminophen-induced Hepatotoxicity}, elocation-id = {mol.112.079863}, year = {2012}, doi = {10.1124/mol.112.079863}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {cJun-NH2-terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that Apoptosis Signal Regulating Kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the MAP3K that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation which in turn promotes mitochondrial dysfunction resulting in amplification of oxidative stress. Thus inhibition of the initial phase of JNK activation may be key to protect against APAP-induced liver injury. The goal of this study was to determine if Mixed-Lineage Kinase 3 (MLK3) mediates the initial ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 is activated by oxidative stress and is required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of Receptor Interacting Protein 1 (RIP1). Moreover, JNK and GSK3βactivation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3 KO mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase (GCL), accelerated hepatic glutathione recovery, and decreased ROS production after APAP treatment. Importantly, MLK3 deficient mice were significantly protected from APAP-induced liver injury compared to wild-type mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity and suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2012/08/23/mol.112.079863}, eprint = {https://molpharm.aspetjournals.org/content/early/2012/08/23/mol.112.079863.full.pdf}, journal = {Molecular Pharmacology} }