Bcl-2 proteins are key regulators of apoptosis in animals as diverse as Caenorhabditis elegans and mammals. This commentary is written in honor of Stan Korsmeyer, whose name we automatically associate with Bcl-2 proteins. Stan Korsmeyer's work was instrumental in the identification and functional characterization of mammalian Bcl-2, the founding member of the family of Bcl-2 proteins, as well as of Bax-like and BH3-only proteins.1, 2, 3, 4 In addition, important concepts of apoptosis regulation, for example the realization that pro- and antiapoptotic Bcl-2 proteins antagonize each others’ functions, emerged from his studies.5 This pioneering work forms the foundation of our current understanding of Bcl-2 proteins and, as discussed below, continues to provide inspiration for those seeking to expand our knowledge regarding this important protein family.

An active role for mitochondria in apoptosis induction is well established in mammals. 6, 7 In many types of mammalian cells, the release of cytochrome c from the mitochondrial intermembrane space (IMS) in response to apoptotic stimuli is required for the assembly and activity of the apoptosome, which is composed of the adaptor protein Apaf-1 and the initiator caspase Caspase-9.8 Specifically, cytochrome c released from the IMS binds to WD-40 repeats in the C-terminal half of the Apaf-1 protein, thereby allowing Apaf-1 oligomerization and binding to Caspase-9. The subsequent apoptosome-dependent processing and activation of effector caspases such as Caspase-3 is a necessary event in a cell's commitment to the cell-death fate. Therefore, mitochondria play a crucial, active role in apoptosis induction in mammals.

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