FIGURE 12.

Hypothesis for the role of signal transduction in APAP-induced liver injury. Production and targeting of NAPQI (first hit) to mitochondria leads to ROS production, which then activates extramitochondrial MAPKK kinase upstream of GSK-3β and JNK. Activation of GSK-3β leads to its translocation to mitochondria where it targets Mcl-1 for degradation and activates MAPKK kinase (i.e. MLP and MEKK1) leading to rapid activation of JNK. Subsequently, ROS release activates ASK-1 leading to sustained JNK activation. JNK then leads to loss of GCL-c and JNK translocates to mitochondria in the early and late phases of the evolution of toxicity providing a sustained second hit to mitochondria. Ultimately, the interplay of these effects of GSK-3β and JNK may promote mitochondrial membrane permeability transition pore opening, full collapse of mitochondrial function, and necrotic death.