The aim of this study was to determine the pathogenetic mechanism of autosomal dominant optic atrophy (ADOA). Bioenergetic failure, abnormalities of the mitochondrial network and increased susceptibility to apoptosis have all been proposed as possible pathogenetic mechanisms. However, the prominent susceptibility of the retinal ganglion cell in this disease remains unclear. We report the clinical features of an ADOA family with a novel deletion of OPA1 gene in the GTPase domain, and investigate mitochondrial morphology and bioenergetics in cells derived from these patients. Muscle biopsy showed neurogenic atrophy and abnormal distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts. In differentiated myotubes, mitochondria were unevenly distributed, with clustered organelles alternating with areas of mitochondrial dearth. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro apoptotic stimuli. The observed mitochondrial network disruption appeared a primary event. This phenomenon, independently of bioenergetics defects, might provide an explanation for the predominant retinal ganglion cell degeneration, whose function may depend on the fine positioning of mitochondria in the axons.

Dominant optic atrophy caused by a novel OPA1 mutation: Disruption of the mitochondrial network with preserved bioenergetics.

SPINAZZI, MARCO;BORTOLOZZI, MARIO;LORO, EMANUELE;MALENA, ADRIANA;SCORRANO, LUCA;ANGELINI, CORRADO;VERGANI, LODOVICA
2008

Abstract

The aim of this study was to determine the pathogenetic mechanism of autosomal dominant optic atrophy (ADOA). Bioenergetic failure, abnormalities of the mitochondrial network and increased susceptibility to apoptosis have all been proposed as possible pathogenetic mechanisms. However, the prominent susceptibility of the retinal ganglion cell in this disease remains unclear. We report the clinical features of an ADOA family with a novel deletion of OPA1 gene in the GTPase domain, and investigate mitochondrial morphology and bioenergetics in cells derived from these patients. Muscle biopsy showed neurogenic atrophy and abnormal distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts. In differentiated myotubes, mitochondria were unevenly distributed, with clustered organelles alternating with areas of mitochondrial dearth. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro apoptotic stimuli. The observed mitochondrial network disruption appeared a primary event. This phenomenon, independently of bioenergetics defects, might provide an explanation for the predominant retinal ganglion cell degeneration, whose function may depend on the fine positioning of mitochondria in the axons.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/180861
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