Figure 4. Regulation of mitochondrial apoptosis by ceramide.

Ceramide can regulate apoptosis via multiple mechanisms. Elevated ceramide levels controls MOMP, and subsequent cytochrome c release by BAX oligomerization and ceramide channel formation. In addition, ceramide-induced activation of PKC-ζ induces BAK oligomer formation and MOMP via AKT inhibition and JNK activation, whereas activation of PKC-δ leads to cytochrome c release from mitochondria to cytosol. On the other hand, dephosphorylation of SR protein or GSK-3β by ceramide-activated protein phosphatase PP1 and PP2A, respectively, results in activation of effectors caspases. Ceramide acts as activation of the protease cathepsin D, which in turn cleaves BID to its active form resulting in caspase activation.