Autosomal Dominant Optic Atrophy is the most commonly inherited form of optic atrophy. One of the main causes of this disease are mutations in OPA1, a gene which encodes the mitochondrial-resident enzyme Opa1. Opa1 is responsible for joining together the inner membranes of separate mitochondria which are in the process of undergoing inner mitochondrial fusion reactions. The inability to undergo fusion is suspected to cause the mitochondria to collapse. Mutations in Opa1 are believed to be associated with such damaging effects that prohibit the visual transmission to pass from the rods and cones to the optic nerve, thus explaining the role mutations play in loss of vision. One location in the enzyme where disease-causing mutations are especially enriched is a region which we believe is involved in direct interactions with the mitochondrial membrane. This region contains similar amino acid sequences with other, related enzymes which are well studied in their interactions with membranes. To determine the role that some of these disease-causing mutations (namely C841-L887del and R836W) play in disease, we will study them <i>in vitro</i> by probing the enzymatic rate, self-assembly, and lipid interactions. We speculate that mutations in the predicted lipid-interacting region of Opa1 will result in no changes to self-interaction, but that there will be decreased binding to certain membrane lipids. The R836W mutation was successfully cloned, but due to complications with a nonsense mutation in the master stock, we are going to have to continue to attempt to clone the mutants into the Opa1 plasmid.

Exploring disease-linked mutations in a predicted lipid-binding domain of Opa1

ACS Spring 2022

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