MITOCHONDRIA AND APOPTOSIS

Programmed cell death serves as a major mechanism for the precise regu lation of cell numbers and as a defense mechanism to remove unwanted a nd potentially dangerous ells. Despite the striking heterogenity of ce ll death induction pathways, the execution of the death program is oft en associated with characteristic morphological and biochemical change s, and this form of programmed cell death has been termed apoptosis. G enetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential fo r cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activa tion of the death program. Caspases (cysteine aspartases) are the mamm alian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the firs t discovered mammalian cell death regulator. In both worm and mammalia n cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processin g into active killers. Two main mechanisms of action have been propose d to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2 s would maintain cell survival by dragging caspases to intracellular m embranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosi s protease-activating factor 1) could be the mammalian equivalent of C ED-4 and could be the physical link between Bcl-2s and caspases. In th e second one, Bcl-2 would act by regulating the release from mitochond ria of some caspases activators: cytochrome c and/or AIF (apoptosis-in ducing factor). This crucial position of mitochondria in programmed ce ll death control is reinforced by the observation that mitochondria co ntribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, w e examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the roaintenance of the symbiosis between the bacterial a ncestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival .