Caspase-8 (red) normally homes in on mitochondria (green) but diffuses widely when mature cardiolipin is absent (right).
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.
