Mitochondria are intact in neurons dying from GDNF deprivation.

On page 987, Yu et al. identify a novel cell death pathway that bypasses mitochondria. The results indicate that various strategies exist to kill off neurons.

A lot of the killing of sympathetic neurons occurs in the first week after birth. During that paring period, ∼50% of sympathetic neurons die due to a lack of nerve growth factor (NGF). Neurons deprived of NGF in vitro die through the classical cell death pathway, which includes the release of cytochrome c from mitochondria and the resulting activation of caspases. Other factors can also promote neuronal survival, but it now seems that the method used to kill cells after withdrawal of these factors is not the same.

Yu et al. find that depriving sympathetic neurons in vitro of GDNF kills cells without mitochondrial involvement. Different caspases were activated than in NGF-dependent neurons, cytochrome c was not released, and mitochondrial structure was maintained in GDNF-deprived neurons.

Initiation of this pathway probably involves the GDNF receptor Ret, which may activate caspase-2 when GDNF is absent. Whether certain neurons depend solely on GDNF for survival in vivo remains to be seen. Perhaps the mitochondria-independent pathway is only a back-up in case the main system fails. But if death pathways are factor- and cell type–specific, some neuronal death might be blocked selectively by interfering with one but not another death pathway. ▪