The point of no return: mitochondria, caspases, and the commitment to cell death.

Apoptosis is a specialized mode of cell death finely regulated at the molecular level and conserved throughout evolution. In many instances during normal development or in order to maintain the homeostasis of a multicellular organism, a strategic intracellular program is initiated ensuring the fate of unwanted cells. Interference with this program has been implicated in many pathologies, particularly in cancer and autoimmune diseases. What is most important, from the organism's point of view, is that the dismissal of the outcast cells is accomplished serenely, i.e., the dying cells resign their existence without causing an inflammatory reaction. Therefore, the ability to manipulate the cell death machinery is an obvious goal of medical research. Here, we debate the idea of the point-of-no-return and propose models for the role of "initiator" and "executioner" caspases in the death program. We argue that, in many circumstances, the cells are committed to die before the execution phase of apoptosis starts. This commitment event is coordinated by the mitochondria and can be blocked by anti-apoptotic oncogenes.