What disease mechanisms contribute to multisystem tissue involvement in dominant optic atrophy due to OPA1 mutations?

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Autosomal dominant optic atrophy (DOA) affects the optic nerve, causing insidious visual loss from early childhood. It is the most common inherited optic nerve disorder and the majority of patients carry mutations in OPA1, a nuclear gene critical for normal mitochondrial function. Mitochondria are essential components of all human cells, containing multiple copies of their own DNA (MtDNA), and forming long branching networks which fuel the cell‘s energy requirements.About 20% of patients with OPA1 mutations will develop a more severe form of the disease (DOA+), associated with a worse visual prognosis and additional neurological complications. The risk of developing DOA+ is three times higher with missense mutations located within the GTPase gene region. Using a range of human tissue samples, I will investigate whether this specific mutational subgroup results in greater fragmentation of the mitochondrial network and more marked mtDNA damage, thus contributing to accelerated cell death. I will also explore the possibility of rescuing the fragmentation defect by manipulating the level of expression of OPA1 and other mitochondrial proteins involved in network fusion and fission. Visual loss in DOA is progressive and the neurological features develop in later life, providing a clear window of opportunity for therapeutic intervention.