Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals?

Abstract

In certain cell types, apoptosis in response to extracellular stimuli like Fas depends on a mitochondrial amplificatory loop: the apical caspase-8 cleaves and activates the BH3-only member of the Bcl-2 family BID. In turn, BID induces the release of cytochrome c from mitochondria to the cytoplasm, where it is required to fully activate effector caspases. In this issue of The Journal of Cell Biology, Gonzalvez et al. (see p. 681) show that when caspase-8 activation and production of functional BID is required, it is performed on mitochondrial platforms provided by the mitochondrion-specific lipid cardiolipin. Cardiolipin anchors caspase-8 at contact sites between inner and outer mitochondrial membranes, facilitating its self activation. These findings suggests that like other second messengers such as Ca(2+) and cAMP, production of apoptotic messengers can be compartmentalized in close proximity to their intracellular target.

Figure 1.

Localized production of active, cleaved BID on cardiolipin platforms that are used for the assembly of active caspase 8. The diagram depicts the sequence of events that occur in type II cells according to Gonzalvez et al. (2008). DD, death domain; DED, death effector domain; p10 and p18 are the catalytic core of the caspase. The p43/p10 caspase 8 isoform comprises two DEDs, one p10, and one p18 domain. The cardiolipin (yellow heads) platform at the contact sites between inner and outer mitochondrial membranes is used to produce active BID where it is needed. This in turn causes BAK/BAX oligomerization and cytochrome c release.