Anand et al. reveal how a GTPase that promotes mitochondrial fusion is proteolytically cleaved to generate a shorter protein that stimulates the organelle’s fission.
Mitochondria constantly fuse and split apart to maintain the organelle’s function and regulate various cellular processes such as apoptosis. The dynamin-like GTPase OPA1 promotes fusion of the mitochondrial inner membrane. The full-length, membrane-bound form of OPA1 (L-OPA1) can be cleaved into a shorter, soluble fragment (S-OPA1) by the protease YME1L and, in response to stress, by OMA1. Mitochondrial fusion is thought to require both L- and S-OPA1, and, accordingly, when the balance of these isoforms is perturbed in cells lacking YME1L, the mitochondrial network becomes fragmented.
Anand et al. found, however, that completely inhibiting the generation of S-OPA1 by removing OMA1 from YME1L-null cells restored the formation of mitochondrial tubules. L-OPA1 was sufficient to promote mitochondrial fusion in these cells. In contrast, the researchers discovered that S-OPA1 is associated with mitochondrial fission. YME1L-null fibroblasts have fragmented mitochondria because OMA1 is hyperactive in these cells, generating excess S-OPA1.
OPA1 processing therefore regulates the balance of mitochondrial fission and fusion. Senior author Thomas Langer now wants to investigate how S-OPA1 promotes the organelle’s fragmentation.
Text by Ben Short