Journal Article

<i>OPA1</i> mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion

Claudia Zanna, Anna Ghelli, Anna Maria Porcelli, Mariusz Karbowski, Richard J. Youle, Simone Schimpf, Bernd Wissinger, Marcello Pinti, Andrea Cossarizza, Sara Vidoni, Maria Lucia Valentino, Michela Rugolo and Valerio Carelli

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 2, pages 352-367
Published in print February 2008 | ISSN: 0006-8950
Published online December 2007 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awm335

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Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to optic neuropathy. A subset of DOA is caused by mutations in the OPA1 gene, encoding for a dynamin-related GTPase required for mitochondrial fusion. The functional consequences of OPA1 mutations in DOA patients are still poorly understood. This study investigated the effect of five different OPA1 pathogenic mutations on the energetic efficiency and mitochondrial network dynamics of skin fibroblasts from patients. Although DOA fibroblasts maintained their ATP levels and grew in galactose medium, i.e. under forced oxidative metabolism, a significant impairment in mitochondrial ATP synthesis driven by complex I substrates was found. Furthermore, balloon-like structures in the mitochondrial reticulum were observed in galactose medium and mitochondrial fusion was completely inhibited in about 50% of DOA fibroblasts, but not in control cells. Respiratory complex assembly and the expression level of complex I subunits were similar in control and DOA fibroblasts. Co-immunoprecipitation experiments revealed that OPA1 directly interacts with subunits of complexes I, II and III, but not IV and with apoptosis inducing factor. The results disclose a novel link between OPA1, apoptosis inducing factor and the respiratory complexes that may shed some light on the pathogenic mechanism of DOA.

Keywords: OPA1; DOA; oxidative phosphorylation; mitochondrial fusion; AIF

Journal Article.  8113 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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