BAX-INDUCED CYTOCHROME-C RELEASE FROM MITOCHONDRIA IS INDEPENDENT OF THE PERMEABILITY TRANSITION PORE BUT HIGHLY DEPENDENT ON MG2+ IONS

Bcl-2 family members either promote or repress programmed cell death. Bar, a death-promoting member, is a pore-forming, mitochondria-associa ted protein whose mechanism of action is still unknown. During apoptos is, cytochrome C is released from the mitochondria into the cytosol wh ere it binds to APAF-1, a mammalian homologue of Ced-4, and participat es in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial pe rmeability transition pore (PTP). We now report that Bar is sufficient to trigger the release of cytochrome C from isolated mitochondria. Th is pathway is distinct from the previously described calcium-inducible , cyclosporin A-sensitive PTP. Rather, the cytochrome C release induce d by Bar is facilitated by Mg2+ and cannot be blocked by PTP inhibitor s. These results strongly suggest the existence of two distinct mechan isms leading to cytochrome C release: one stimulated by calcium and in hibited by cyclosporin A, the other Bar dependent, Mg2+ sensitive but cyclosporin insensitive.