Gonzalvez et al. reveal that a mitochondrial lipid provides a gathering place where the enzymes can mingle.
After receiving an external death signal, cells can commit suicide in several ways. In one mechanism, inactive copies of caspase-8 gather at the death-inducing signaling complex (DISC) on the cell membrane. There, the molecules combine and cut one another, becoming active enzymes.
But in an alternative mechanism, Gonzalvez et al. showed that caspase-8 migrates to the mitochondria instead of combining at the DISC. While probing the function of cardiolipin, a mitochondrial membrane lipid, Gonzalvez et al. discovered how caspase-8 molecules meet up at this organelle.
The researchers tested cells from patients with Barth syndrome, a rare genetic disorder in which the functional form of cardiolipin is scarce. The cells survived treatment with apoptosis-triggering molecules such as TNFα. Without mature cardiolipin, caspase-8 doesn't embed in the mitochondrial membrane and doesn't get activated, the scientists found.
Cardiolipin seems to serve as the mitochondrial equivalent of the DISC, a platform where caspase-8 molecules can collect and undergo the modifications necessary for activation. Still unclear is what signal directs caspase-8 to the mitochondria and whether other caspases also travel to the organelles to be switched on.