Apoptosis: checkpoint at the mitochondrial frontier

Apoptosis, an evolutionarily conserved form of cell death, requires a regul ated program. Central to the apoptotic program is a family of cysteine prot eases, known as caspases, that cleave a subset of cellular proteins, result ing in the stereotypic morphological changes of apoptotic cell death. In li ving cells caspases are present as inactive zymogens and become activated i n response to pro-apoptotic stimuli. Mitochondria participate in the activa tion of caspases by releasing cytochrome c into the cytosol where it binds to the adaptor molecule Apaf-1 (apoptotic protease activating factor 1) and causes its oligomerization. This renders Apaf-1 competent to reemit and ac tivate the cell death initiator caspase, pro-caspase-9. Once caspase-9 is a ctivated, it cleaves and activates downstream cell death effector caspases. Bcl-2, an apoptosis inhibitor localized to mitochondrial outer membranes, prevents cytochrome c release, caspase activation and cell death. This revi ew discusses recent advances on the role of mitochondria and cytochrome c i n the central pathway leading to apoptotic cell death. (C) 1999 Elsevier Sc ience B.V. All rights reserved.