Apoptosis pathways: turned on their heads?

Apoptotic pathways are thought to be initiated at the plasma membrane (receptor pathway) or at the mitochondria (mitochondrial pathway) and to ultimately converge in the activation of caspases, a family of cysteine proteases. On p. 1, Fulda and Debatin comment on recent reports of DNA damage leading first to caspase-2 activation and then triggering mitochondrial permeability. The studies, in which small interfering RNA (siRNA) was used to selectively block the expression of individual apoptotic proteins, raise the possibility of caspase activation occurring upstream of mitochondria, at least in some cells.