The mitochondrion in cell death control: Certainties and incognita

Apoptosis research has recently experienced a change from a paradigm in whi ch the nucleus determined the apoptotic process to a paradigm in which casp ases and, more recently, mitochondria constitute the center of death contro l. Mitochondria undergo major changes in membrane integrity before classica l signs of cell death become manifest. These changes concern both the inner and the outer mitochondrial membranes, leading to the dissipation of the i nner transmembrane potential (Delta Psi(m)) and/or the release of intermemb rane proteins through the outer membrane. An ever-increasing number of endo genous, viral, or xenogeneic effecters directly act on mitochondria to trig ger permeabilization. At least in some cases, this is achieved by a direct action on the permeability transition pore complex (PTPC), a multiprotein e nsemble containing proteins from both mitochondrial membranes, which intera ct with pro- and antiapoptotic members of the Bcl-2 family. At present, it is elusive whether opening of the PTPC is the only physiological mechanism leading to mitochondrial membrane permeabilization. Proteins released from mitochondria during apoptosis include caspases (mainly caspases 2, 3, and 9 ), caspase activators (cytochrome c, hsp 10), as well as a caspase-independ ent death effector, AIF (apoptosis inducing factor). The functional hierarc hy among these proteins and their actual impact on the decision between dea th and life is elusive. (C) 2000 Academic Press.