MOMP, cell suicide as a BCL-2 family business

Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.