231. Artal-Sanz et al. show that cells are more likely to escape a necrotic death sentence if they contain less acidic lysosomes.
Necrosis—considered the unprogrammed counterpart to apoptotic death—is the deadly result of a severe and abrupt loss of energy, nutrients, or oxygen. These stimuli create sudden alterations in intracellular pH or ion levels that ultimately turn on destructive proteases within the cell.
Some of these proteases, such as cathepsins, work best at very low pH. Acidification of the cell occurs during necrosis. Further, a pump that acidifies lysosomes, where cathepsins are normally sequestered, is required for necrosis in worms.
The new study shows that lysosomes are themselves needed during necrosis. By interfering with lysosomal biogenesis, the authors hindered neuronal necrosis in worms. Mutations that created abnormally large lysosomes, by contrast, aggravated necrosis.
Lysosomes also have to be acidified to be necrosis inducing. The authors found that alkalization of the organelles using weak bases suppressed necrosis. It also further reduced death in mutant neurons with unusually low amounts of cathepsins.
The authors suspect that lysosomes start leaking their contents at early stages of necrosis. Their idea is supported by past evidence that the protease calpain—which is activated by high Ca2+ levels during necrosis—damages lysosomal membranes. The damage might open the door for a slow escape of cathepsin and H+—thus both freeing proteases that dismantle the cell and creating the acidic environment in which they thrive. At later stages of death, the authors saw, lysosomes ruptured completely.
Necrosis dominates the neuronal death caused by ischemia during a stroke. Perhaps the damage can be minimized if therapies are devised to prevent lysosomal acidification locally. The drugs would probably only be beneficial, however, if administered very shortly after the stroke.