OMA1 promotes neurodegeneration by tipping the balance between mitochondrial fusion and fission, Korwitz et al. reveal.
OPA1 is one of the key proteins that controls mitochondrial morphology. The protein comes in a long form, which promotes mitochondrial fusion, and a short form, which researchers think spurs fission. Stressed cells often break up their mitochondrial network, activating OMA1, a protease that cleaves OPA1 and helps produce the short version. OMA1-induced mitochondrial breakup is essential for mitophagy and cell death in vitro, but its role in vivo remains unclear.
Korwitz et al. probed OMA1’s function in mice that lack the mitochondrial protein prohibitin 2 in the forebrain. Levels of the long form of OPA1 decline in these mice, and they therefore develop fatal neurodegeneration. However, when the researchers removed OMA1 from the rodents, their lifespan was significantly extended. Deleting OMA1 allowed the animals to maintain the long form of OPA1 and thwarted formation of the short form.
Mice lacking prohibitin 2 have small brains, but animals that were also missing OMA1 had normal sized brains, suggesting that the loss of OMA1 protects neurons from apoptosis.
Removal of OMA1 also prevented the cells’ mitochondrial DNA from deteriorating. However, mitochondria from animals lacking OMA1 and prohibitin 2 weren’t normal—they were huge and lacked cristae. The results show that by limiting mitochondrial fusion, OMA1 can trigger cell death and neurodegeneration. However, researchers still need to determine what circumstances lead to activation of the protease in vivo.
Text by Mitch Leslie