title: OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion.
abstract: 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.
authors.affiliation: Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Via Irnerio 42, 40126 Bologna, Italy. zanna@alma.unibo.it
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Simone
authors.initials: S
authors.lastname: Schimpf
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Marcello
authors.initials: M
authors.lastname: Pinti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.forename: Sara
authors.initials: S
authors.lastname: Vidoni
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000032:analysis; D004579:Electron Transport; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D012867:Skin / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D004272:DNA, Mitochondrial; D016877:Oxidants; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human