title: A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function.
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.
authors.affiliation: Neurosciences Department, University of Padova, Italy. marco.spinazzi@unipd.it
authors.forename: Marco
authors.initials: M
authors.lastname: Spinazzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Cazzola
authors.forename: Mario
authors.initials: M
authors.lastname: Bortolozzi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baracca
authors.forename: Emanuele
authors.initials: E
authors.lastname: Loro
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Solaini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sgarbi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casalena
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Adriana
authors.initials: A
authors.lastname: Malena
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.forename: Franco
authors.initials: F
authors.lastname: Carrara
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D004734:Energy Metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000201:enzymology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000473:pathology; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human