Objectif Autosomal dominant optic atrophy (ADOA) is caused by mutations in Optic Atrophy 1 (OPA1), a dynamin-related protein of the inner mitochondrial membrane. During the last years, we clarified that OPA1 is a multifunctional protein participating in genetically distinct pathways of mitochondrial fusion and cristae remodelling, both impaired by pathogenetic mutations. We extended our investigation on the (dys)function of OPA1 and our preliminary results indicate that (i) OPA1 is a key modulator of apoptosis and autophagy in vivo; (ii) OPA1 is a master regulator of mitochondrial cristae architecture, impacting on respiratory chain supercomplex assembly and mitochondrial metabolism; (iii) increased autophagy in axons of retinal ganglion cells carrying pathogenic OPA1 depletes them of mitochondria; (iv) OPA1 resides in multimolecular complexes that comprise potential keyregulators of its multiple functions. We therefore hypothesize that by engaging in interactions with different partners, OPA1 regulates mitochondrial functions. Its mutations increase autophagy and susceptibility to apoptosis, especially in RGCs. These multiple regulatory points offer several potential targets for therapeutic strategies that can interfere with the natural course of the disease. In order to verify our hypothesis, we plan to address: (i) how OPA1 regulates mitochondrial metabolism from the cristae; (ii) how changes in OPA1 levels and function impinge on autophagy, especially in RGC; (iii) if the changes in mitochondrial metabolism and autophagy can be exploited therapeutically in vitro and in vivo. This integrated approach aims at unraveling the pathogenesis of ADOA, and therefore to pave the way for its treatment. At the same time, we expect to clarify how mitochondria participate in key cellular metabolic and quality control processes. Champ scientifique natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutation Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2013-CIG - Marie-Curie Action: "Career Integration Grants" Appel à propositions FP7-PEOPLE-2013-CIG Voir d’autres projets de cet appel Régime de financement MC-CIG - Support for training and career development of researcher (CIG) Coordinateur UNIVERSITA DEGLI STUDI DI PADOVA Contribution de l’UE € 100 000,00 Adresse VIA 8 FEBBRAIO 2 35122 Padova Italie Voir sur la carte Région Nord-Est Veneto Padova Type d’activité Higher or Secondary Education Establishments Contact administratif Emanuela Pavia (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée