OPA1 · OPA1 in dominant optic atrophy

Final Activity Report Summary - OPA1 (OPA1 in Dominant Optic Atrophy)

The ultimate goal of this project was to investigate the molecular mechanism underlying autosomal Dominant Optic Atrophy (DOA), a devastating genetic disorder leading to degeneration of retinal ganglion cells and childhood blindness. The gene defective in DOA maps to chromosome 3q28-29 and is called Optic Atrophy type 1 (OPA1). OPA1 encodes a mitochondrial membrane protein that carries several mutations in humans with DOA. OPA1 facilitates membrane fusion events that are required for mitochondrial integrity and maintenance. Loss of OPA1 function leads to mitochondrial fission, loss of mitochondrial DNA, and respiratory deficits. Mitochondrial dysfunction in turn leads to loss of retinal ganglion cells and degeneration of optical neurons that result in blindness. OPA1 is a 961 amino acid residue protein that belongs to a family of highly conserved GTPases related to Dynamin. Intriguingly, the majority of missense mutations found in DOA patients reside in the highly conserved GTPase domain. In order to unravel the molecular mechanism underlying mitochondrial fusion and to set the groundwork for the development of DOA therapies, a detailed understanding of OPA1 function is necessary. To achieve this, we undertook a functional characterization of OPA1 by means of biochemical and structural studies. During this MCIRG project we pursued the following aims: Specific Aim #1: Biochemical and biophysical characterisation of OPA1 with regards to GTPase activity, function, and activation. Specific Aim #2: Biochemical and biophysical characterisation of DOA mutations in OPA1. Specific Aim #3: Structural basis of OPA1 function. In our work we could show that: #1 OPA1 is a mechano-enzyme that uses GTP hydrolysis to switch between distinct conformations that either facilitate membrane fusion directly or recruit machinery for it. #2 GTPase activity is critical for OPA1 function and DOA miss-sense mutations located in the GTPase active site impair GTP hydrolysis and lock the protein in an 'on' or 'off'- state. We are currently working on the OPA1 crystal structure determination which will reveal the architecture of this remarkable mechano-enzyme. The structure of the parts that are N- and C-terminal to the GTPase domain will shed light on the molecular details of how OPA1 facilitates the mitochondrial fusion process. The results produced during this project served as preliminary results for a project grant that will allow us to continue this work.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз