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Extending the Optic atrophy 1 dependent cristae remodeling: from models to a rationale for therapy of autosomal dominant optic atrophy (cristopa1)
Start date: Oct 1, 2013, End date: Sep 30, 2017 PROJECT  FINISHED 

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.

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