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. |