MITOCHONDRIAL APOPTOTIC PATHWAYS AND MITOCHONDRIAL REMODELLING IN DOMINANT OPTIC ATROPHY

Dominant optic atrophy (OPA) is the most common genetic disease that results in loss of vision as a consequence of degeneration of the neurons that connect the eye with the brain. Since this loss occurs in the absence of pain and inflammation, it is conceivable that this involves a particular form of death of the cells, called apoptosis. Apoptosis is essential for the correct development of all multicellular organisms, but when dysregulated can lead to a wide range of conditions, from neurodegenerative diseases to cancer. Mitochondria, the powerhouses of the cell, crucially control apoptosis, by releasing some proteins into the cytosol, where they activate caspases, proteins that literally cut the components of the cell ultimately culminating in its death. These mitochondrial proteins are normally sequestered in complex internal structures of the mitochondria, called cristae, which resemble little bags connected with the outside by a tight bottleneck that needs to be opened to allow the efflux of the proteins during apoptosis. OPA is the consequence of mutations in a gene that codes for a mitochondrial protein, OPA1, whose role is to control the complicate internal shape of mitochondria. Very little is known on how the mutations identified in the OPA1 gene lead to the clinical disease. We propose to investigate if and how diseased OPA1 causes increased apoptosis and ultimately loss of the neurons that transport the visual signal from the eye to the brain. By accomplishing this, we will provide a mechanism that can be targeted by rationally designed drugs, so that we can stop or slow the progression of the disease.