[Mitochondrial control of apoptosis].

The dysregulation of programmed cell death (apoptosis) is involved in different pathologies including cancer, which is frequently associated with an increase resistance to apoptosis induction. We discovered in 1994 the implication of a specific organelle, the mitochondrion, in apoptosis. Our result have demonstrated that mitochondrial membrane permeabilization (MMP) constitutes a decisive step of the apoptotic process. MMP is regulated by numerous effectors, including the proteins from the Bcl-2/Bax family (oncogenes or tumor suppressor genes which modulate apoptosis), which interact with sessile proteins of mitochondria. MMP can be induced by a large number of pro-apoptotic second messengers, as well as by some experimental anti-cancer agents, suggesting that MMP constitutes a point of integration of the apoptotic response. As a result of MMP, several apoptogenic proteins normally confined to mitochondria are released in the extra-mitochondrial space and participate in the suicidal dismantling of the cell. We have identified several mitochondrial apoptogenic proteins, one of which, the apoptosis inducing factor (AIF) has been cloned. AIF appears to be one of the principal effectors of the apoptotic machinery. Genetic inactivation of AIF abolishes the first wave of apoptosis indispensable for early embryonic morphogenesis. In contrast, its presence in the extra-mitochondrial compartment suffices to kill cells. Altogether, these results allow for the development of new strategies aiming at inducing apoptosis in cancer cells.