Human Molecular Genetics Advance Access published online on August 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn225
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A NOVEL DELETION IN THE GTPase DOMAIN OF OPA1 CAUSES DEFECTS IN MITOCHONDRIAL MORPHOLOGY AND DISTRIBUTION, BUT NOT IN FUNCTION
1 Neurosciences Department, University of Padova, Italy 2 Venetian Institute of Molecular Medicine, Padova; 3 Department of Biochemistry, University of Bologna, Italy 4 Department of Pediatrics, University of Padova 5 Department of Radiological and Histocytopathological Sciences, University of Bologna 6 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova 7 Istituto Neurologico C. Besta, Milano, Italy
* To whom correspondence should be addressed at: Clinica Neurologica II, Via Facciolati 71, 35100, Padova, Italy. Tel: +39/049/8215315; Fax: +39/049/8215310; Email: marco.spinazzi{at}unipd.it
Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed as possible causal factors. However, their relative contribution to pathogenesis as well as the prominent susceptibility of the retinal ganglion cell in this disease remain uncertain. Here we identify a novel deletion of OPA1 gene in the GTPase domain in three patients affected by ADOA.
Muscle biopsy of the patients showed neurogenic atrophy and abnormal morphology and distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts as well as in myotubes, where mitochondria were also unevenly distributed, with clustered organelles alternating with areas where mitochondria were sparse. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro-apoptotic stimuli. Therefore, the changes in mitochondrial shape and distribution can be independent of other reported effects of OPA1 mutations, and therefore may be the primary cause of the disease. The arrangement of mitochondria in retinal ganglion cells, which degenerate in ADOA, may be exquisitevely sensitive to disturbance, and this may lead to bioenergetic crisis and/or induction of apoptosis. Our results highlight the importance of mitochondrial dynamics in the disease per se, and point to the loss of the fine positioning of mitochondria in the axons of retinal ganglion cells as a possible explanation for their predominant degeneration in ADOA.
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