Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death

Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis and tissue homeostasis, In mammals, release of mitochondrial cytochrome c leads to the cytosolic assembly of the apoptosome - a caspase activation complex involving Apaf1 and caspase-9 that induces hallmarks of apoptosis, There are, however, mitochondrially regulated cell death pathwa ys that are independent of Apaf1/caspase-9, We have previously cloned a mol ecule associated with programmed cell death called apoptosis-inducing facto r (AIF), Like cytochrome c,AIF is localized to mitochondria and released in response to death stimuli. Here we show that genetic inactivation of AIF r enders embryonic stem cells resistant to cell death after serum deprivation , Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies-the very first wave of cell death indispensable for mouse morphogenesis, AIF-dependent cell death displays structural features of apo ptosis, and can be genetically uncoupled from Apaf1 and caspase-9 expressio n. Our data provide genetic evidence for a caspase-independent pathway of p rogrammed cell death that controls early morphogenesis.