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A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function

Spinazzi, Marco
Cazzola, Silvia
Bortolozzi, Mario
Baracca, Alessandra
Loro, Emanuele
Casarin, Alberto
Solaini, Giancarlo
Sgarbi, Gianluca
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Published in Human molecular genetics. 2008, vol. 17, no. 21, p. 3291-3302
Abstract 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 (RGC) in this disease remains 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, 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 RGCs, which degenerate in ADOA, may be exquisitely 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 RGCs as a possible explanation for their predominant degeneration in ADOA.
Keywords AdolescentAdultApoptosisCells, CulturedChildEnergy MetabolismFemaleGTP Phosphohydrolases/*genetics/metabolismGene Expression Regulation, EnzymologicHumansMaleMiddle AgedMitochondria/*metabolism/pathologyMuscle, Skeletal/abnormalities/enzymologyOptic Atrophy, Autosomal Dominant/*genetics/physiopathologyPedigreeReactive Oxygen Species/metabolismRetina/pathologySequence DeletionYoung Adult
PMID: 18678599
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Other version: http://hmg.oxfordjournals.org/content/17/21/3291.full.pdf
Research group Les mitochondries dans la vie cellulaire (850)
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SPINAZZI, Marco et al. A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. In: Human molecular genetics, 2008, vol. 17, n° 21, p. 3291-3302. doi: 10.1093/hmg/ddn225 https://archive-ouverte.unige.ch/unige:19111

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Deposited on : 2012-03-27

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