FIG. 9.
Mechanism of protection by Antcin H: Inhibition of sustained JNK activation and blocking the binding of p-JNK to mitochondria. The interplay of p-JNK and mitochondrial Sab leads to increased ROS release, which activates the MAPKinase cascade and may inactivate JNK phosphatase (MKP1), leading to a self-perpetuating pathway, which activates mitochondrial ROS production and cytoplasmic JNK activation. Thus, the ROS may then amplify the effects of APAP on mitochondria leading to MPT induction and necrosis. In the APAP model, GSH and ATP depletion and a high level of ROS incapacitate caspase activity. Sustained JNK activation also plays an important role in apoptosis by its known actions on c-FLIP degradation, allowing caspase-8 to cleave Bid to t-Bid, as well as activation of Bax and inactivation of Bcl-XL and Mcl-1, thereby promoting MOMP and cytochrome c release. Antcin H disrupts the ability of p-JNK to interact with mitochondrial Sab, thereby abrogating the mechanism for sustained JNK activation. MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars