Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis.: OPA1: mitochondrial morphology, apoptosis, and optic atrophy
| Autor: | Olichon, Aurélien, Landes, Thomas, Arnauné-Pelloquin, Laetitia, Emorine, Laurent, Mils, Valérie, Guichet, Agnès, Delettre, Cécile, Hamel, Christian, Amati-Bonneau, Patrizia, Bonneau, Dominique, Reynier, Pascal, Lenaers, Guy, Belenguer, Pascale |
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| Přispěvatelé: | Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Hamel, Christian |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
endocrine system
MESH: Mutation Missense MESH: GTP Phosphohydrolases MESH: Humans MESH: Mutation MESH: Mitochondria MESH: Apoptosis MESH: Transfection MESH: Microscopy Fluorescence MESH: Phenotype eye diseases MESH: Optic Atrophy Autosomal Dominant MESH: Hela Cells MESH: Skin MESH: Fibroblasts MESH: Gene Deletion MESH: Staurosporine MESH: Blotting Western [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] |
| Zdroj: | Journal of Cellular Physiology Journal of Cellular Physiology, 2007, 211 (2), pp.423-30. ⟨10.1002/jcp.20950⟩ |
| ISSN: | 0021-9541 1097-4652 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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