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 OPA...

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Bibliographic Details
Published in:Human molecular genetics 2010-06, Vol.19 (11), p.2113-2122
Main Authors: Ban, Tadato, Heymann, Jürgen A.W., Song, Zhiyin, Hinshaw, Jenny E., Chan, David C.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiolipins - metabolism
Cryoelectron Microscopy
Diseases of visual field, optic nerve, optic chiasma and optic tracts
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
Guanosine Triphosphate - metabolism
Hydrolysis
Liposomes - metabolism
Liposomes - ultrastructure
Medical sciences
Mice
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Molecular and cellular biology
Mutation - genetics
Ophthalmology
Optic Atrophy - genetics
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Summary: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 GTPγS. 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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddq088