Figure 1 JNK signaling pathway during APAP-induced liver injury. An overdose of APAP produces excessive NAPQI, depletes GSH in the cytoplasm, endoplasmic reticulum and mitochondria, forms mitochondrial protein adducts, damages the electron transport chain and induces initial oxidative stress and production of ROS. In addition, MAP3K, including MLK3, ASK1 and GSK3β are activated,resulting in JNK activation through MAP2k. Moreover, mTORC1 is inhibited during APAP-induced liver injury and thus inhibiting phosphorylation of ULK1/2, increasing level of activated ULK1/2 which ultimately acts on JNK. Upstream molecules of JNK include RIPK1 and RIPK3. Endoplasmic Reticulum (ER) stress is an important mechanism in APAP-induced liver injury and JNK is a biomarker of ER stress. Notably, phosphorylated JNK translocates to the mitochondria and binds to the adaptor protein, Sab. The downstream molecules of p-JNK, such as Bax and Drp1 are also translocated to the mitochondria. Furthermore, downstream events of p-JNK include PKC-α, CHOP and Bim. Bax mainly induces mitochondrial dysfunction, MPT and continuous production of ROS. In addition, ROS produced in the mitochondria play an essential role in sustaining activation of JNK. Notably, MPT pores open and endonuclease G, cytochrome C and AIF are released into the cytoplasm and translocate to the nucleus. Finally, death or injury of liver cells occurs.
Figure 2 JNK mediates APAP-induced death of liver cells. p-JNK promotes secretion of FasL in an autocrine or paracrine manner. In addition, production of TNF-α and TRAIL increases when inflammation occurs and these molecules are associated with the corresponding death receptors. Moreover, JNK signaling pathway is activated to amplify oxidative stress during APAP-induced hepatotoxicity. Thereafter, JNK mediates death receptor-dependent apoptosis. Additionally, p-JNK translocates to the mitochondria and activates the downstream apoptotic events to mediate apoptosis through the mitochondria/caspase-9 pathway. Furthermore, p-JNK in the mitochondria induces the downstream events in the mitochondria. MPT pores open, mitochondrial respiration is inhibited and ATP synthesis is decreased resulting in insufficient energy for apoptosis. Finally, mitochondrial swelling and oncotic necrosis occurs.