There is more and more evidence for an important role of mitochondria in the propagation of death signals and the final activation of the executing caspase cascadex. Several different apoptosis-inducing stimuli (e.g. Dexamethasone, irradiation, etoposide, anti Fas mAb, TNF-alpha, staurosporine, ceramide) result in mitochondrial Permeability Transition (PT) what mediates the reduction of the mitochondrial transmembrane potential (MTP) (Kroemer, G. et al., 1997, Immun. Today, vol.18 no.1: 44-51). Mitochondria undergoing PT and MTP release mitochondrial proteins (e.g. cytochrome c and AIF) into the cytoplasm. Cytochrome c was shown to bind to Apaf-1 (a mammalian protein with homology to Ced-4) which is (dependent on the presence of dATP) activated to cleave Pro-Caspase-9 (Li, P. et al., 1997, Cell, 91: 479-89). This could be a link between diverse apoptotic stimuli and the initiation of an apoptotic caspase cascade.
Death receptor molecules such as Fas/CD95 that integrate with the
caspases directly via their cytoplasmic tail may either bypass the
requirement for a mitochondrial derived factor or may channel subsequent
signaling events through the mitochondria:
Caspase-8 is proven to be activated by its recruitment to the Death Inducing Signaling Complex (DISC) in Fas-mediated apoptosis. It is thought that upon binding to FADD, caspase-8 undergoes autocatalytic activation. The active caspase-8 (composed of one small and one large subunit) is released from the DISC and triggers the apoptotic caspase cascade: maybe the initiator caspase-8 activates an amplifier caspase (e.g. caspase-1) which in turn activates effector caspases-3, -6 and -7.
The relevance of caspase-1 in the initiation-phase of apoptosis is still somewhat obscure: Caspase-1 (and possibly Caspase-4 and Caspase-5) is probably primarily involved in the activation of proinflammatory cytokines though there exists experimental support for its involvement in apoptosis, in particular Fas/CD95-mediated apoptosis. It was shown that Caspase-1 (or Caspase-1 like proteases) is necessary and sufficient to mediate the mitochondrial Permeability Transition (PT) and the release of AIF from mitochondria in cells subjected to Fas ligation (Susin et al., 1997, J. Exp. Med., vol.186, no.1: 25-37). The PT and AIF release after Fas ligation is prevented by Caspase-1 inhibitors like CrmA or Ac-YVAD-CHO but not by Ac-DEVD-CHO. So Caspase-1 could be the link between the active Caspase-8 at the apex of the Fas pathway and the (putative) general apoptotic checkpoint events (PT, AIF release, Cytochrome c release) at the mitochondrial membrane which result in the activation of Caspase-3 and by this the apoptotic executioner and degradation phase. This model of Fas-mediated apoptosis would also be consistent with the observation that Caspase-1 activity (cleavage of tetrapeptide YVAD) reaches a peak immediately (10-30 min) after Fas ligation while Caspase-3 activity (cleavage of DEVD) is detected 1-2 hours after FAS-ligation (Eari et al., 1996, Naure, vol.380: pp723).
The central involvement of mitochondria in apoptotic pathways would also explain the way in which members of the bcl2 multigene family regulate apoptosis. Bcl-2 for example (which is mainly localized at the outer mitochondrial membrane) is likely to suppress apoptosis via inhibition of the mitochondrial Permeability Transition (PT). Interestingly, in Fas-mediated apoptosis the Caspase-1 induced mitochondrial PT and AIF release is not prevented by Bcl-2, while ceramide-induced or t-BHP-induced PT and AIF release are blocked by Bcl-2. This is consistent with the observation that Bcl-2 is incapable of suppressing the Fas-induced apoptosis in number of different models. In contrast, Bcl-2 efficiently inhibits mitochondrial PT induced by a variety of different stimuli.