The study of apoptosis is synonymous with the nematode Caenorhabditis elegans, as many of the important molecular components in this conserved biological process have been identified through genetic studies in this model organism. Now, reporting in Nature, Barbara Conradt and co-workers show that mitochondrial fragmentation — previously thought to be an exclusive characteristic of apoptotic mammalian cells — is also a feature of apoptosis in C. elegans. And by mutating the tractable genome of this useful organism, the researchers explain how mitochondrial break-up might contribute to the apoptotic process.

Although mitochondria had not previously been shown to have a crucial role in apoptosis in nematodes, it seemed unlikely that this organelle — such an enthusiastic participant in apoptosis in mammals — would be a mere 'innocent bystander' in the C. elegans cell-death programme. So Conradt and her team examined live C. elegans embryos using time-lapse confocal microscopy and noted the morphology of mitochondria in cells that were undergoing programmed cell death. They observed that, in non-apoptotic cells, mitochondria formed a cohesive network of tubules. However, soon after the induction of apoptosis, the network started to break up until only mitochondrial fragments remained in the cell.

But is the fragmentation of mitochondria a causal event in apoptosis, or simply a morphological phenomenon in a dying cell? Conradt and co-workers tackled this question by expressing a dominant-negative mutant of the mitochondrial-fission-promoting protein DRP-1 in C. elegans embryos, thereby inhibiting mitochondrial break-up. This inhibition of mitochondrial fragmentation prevented apoptosis in ∼20% of cells in these transgenic animals. Importantly, the overexpression of wild-type drp-1 during embryogenesis increased mitochondrial disintegration and also increased the number of cells that died by apoptosis.

Using loss-of-function and gain-of-function mutant embryos, the authors deciphered which of the molecular components of the apoptotic pathway affected the break-up of mitochondria, and they incorporate mitochondrial disruption into a new working model of apoptosis in C. elegans. They propose that, in cells that are destined to die, the pro-apoptotic protein EGL-1 binds to, and activates, CED-9. CED-9 then activates DRP-1, which mediates mitochondrial disruption. How exactly mitochondrial fragmentation contributes to cell death in C. elegans remains unclear, but the authors suggest that, as these organelles fragment, a pro-apoptotic molecule might be liberated that potentiates the activity of the adaptor protein CED-4. CED-4 activates the caspase CED-3, and the enhanced activity of this enzyme results in efficient programmed cell death.