OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.
The dynamin-related GTPase OPA1 is mutated in autosomal dominant optic atrophy (DOA) (Kjer type), an inherited neuropathy of the retinal ganglion cells. OPA1 is essential for the fusion of the inner mitochondrial membranes, but its mechanism of action remains poorly understood. Here we show that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids such as cardiolipin. Lipid association triggers assembly of OPA1 into higher order oligomers. In addition, we find that OPA1 can promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies are observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 is suppressed by GTPgammaS. OPA1 disease alleles associated with DOA display selective defects in several activities, including cardiolipin association, GTP hydrolysis and membrane tubulation. These findings indicate that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis and lead to membrane deformation into tubules.
Ban
Tadato
T
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Heymann
Jürgen A W
JA
Song
Zhiyin
Z
Hinshaw
Jenny E
JE
Chan
David C
DC
D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D020285:Cryoelectron Microscopy; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006868:Hydrolysis; D008081:Liposomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D009896:Optic Atrophy / Q000235:genetics*
D002308:Cardiolipins; D008081:Liposomes; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse