title: Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis.
abstract: To characterize the molecular links between type-1 autosomal dominant optic atrophy (ADOA) and OPA1 dysfunctions, the effects of pathogenic alleles of this dynamin on mitochondrial morphology and apoptosis were analyzed, either in fibroblasts from affected individuals, or in HeLa cells transfected with similar mutants. The alleles were missense substitutions in the GTPase domain (OPA1(G300E) and OPA1(R290Q)) or deletion of the GTPase effector domain (OPA1(Delta58)). Fragmentation of mitochondria and apoptosis increased in OPA1(R290Q) fibroblasts and in OPA1(G300E) transfected HeLa cells. OPA1(Delta58) did not influence mitochondrial morphology, but increased the sensitivity to staurosporine of fibroblasts. In these cells, the amount of OPA1 protein was half of that in control fibroblasts. We conclude that GTPase mutants exert a dominant negative effect by competing with wild-type alleles to integrate into fusion-competent complexes, whereas C-terminal truncated alleles act by haplo-insufficiency. We present a model where antagonistic fusion and fission forces maintain the mitochondrial network, within morphological limits that are compatible with cellular functions. In the retinal ganglion cells (RGCs) of patients suffering from type-1 ADOA, OPA1-driven fusion cannot adequately oppose fission, thereby rendering them more sensitive to apoptotic stimuli and eventually leading to optic nerve degeneration.
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université Paul Sabatier, Toulouse, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Olichon
authors.forename: Thomas
authors.initials: T
authors.lastname: Landes
authors.forename: Laetitia
authors.initials: L
authors.lastname: Arnauné-Pelloquin
authors.forename: Laurent J
authors.initials: LJ
authors.lastname: Emorine
authors.forename: Valérie
authors.initials: V
authors.lastname: Mils
authors.forename: Agnès
authors.initials: A
authors.lastname: Guichet
authors.forename: Cécile
authors.initials: C
authors.lastname: Delettre
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.forename: Pascale
authors.initials: P
authors.lastname: Belenguer
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D019311:Staurosporine