Mitochondrial control of apoptosis

The dysregulation of programmed cell death (apoptosis) is involved in diffe rent pathologies including cancer, which is frequently associated with an i ncrease resistance to apoptosis induction. We discovered in 1994 the implic ation of a specific organelle, the mitochondrion, in apoptosis. Our result have demonstrated that mitochondrial membrane permeabilization (MMP) consti tutes a decisive step of the apoptotic process. MMP is regulated by numerou s effectors, including the proteins from the Bcl-2/Bax family (oncogenes or tumor suppressor genes which modulate apoptosis), which interact with sess ile proteins of mitochondria. MMP can be induced by a large number of pro-a poptotic second messengers, as well as by some experimental anti-cancer age nts, suggesting that MMP constitutes a point of integration of the apoptoti c response, As a result of MMP, several apoptogenic proteins normally confi ned to mitochondria are released in the extra-mitochondrial space and parti cipate in the suicidal dismantling of the cell. We have identified several mitochondrial apoptogenic proteins, one of which, the apoptosis inducing fa ctor (AIF) has been cloned AIF appears to be one of the principal effectors of the apoptotic machinery. Genetic inactivation of AIF abolishes the firs t wave of apoptosis indispensable for early embryonic morphogenesis. In con trast, its presence in the extra-mitochondrial compartment suffices to kill cells. Altogether, these results allow for the development of new strategi es aiming at inducing apoptosis in cancer cells.