Investigating the distinct regulatory roles of the paralogs Slc25a12 and Slc25a13 on Malate-Aspartate shuttle activity and Opa1-mediated cristae remodeling

Mitochondria are double membrane organelles that serve as the cells bioenergetic units of life. While the outer mitochondrial membrane is permeable to ions and molecules, the inner mitochondrial membrane (IMM) is highly selective and requires specialized transport proteins to exchange metabolites into the mitochondrial matrix. The Slc25a family represents the largest group of solute carriers of the IMM. Aralar (Slc25a12, Agc1) and citrin (Slc25a13, Agc2) are paralogs with distinct tissue expression patterns, but with the same carrier function importing glutamate and a proton into the matrix in exchange for aspartate export. Both are also components of the malate-aspartate shuttle which transfers cytosolic NADH into mitochondria linking glycolysis to the tricarboxylic acid cycle. Optic Atrophy 1 (Opa1), a dynamin-related IMM protein regulates IMM architecture and its oligomeric status is regulated by metabolic changes that remodel cristae. Current research in the Scorrano laboratory demonstrates aralar directly interacts with Opa1 and contributes to cristae maintenance. CRISPR-Cas9 deletion of Agc1 reduced Opa1 protein levels, impaired Opa1 oligomerization, and reduced cristae density. This internship investigated whether a pathogenic variant of aralar that lacks transport activity can mediate Opa1-dependent cristae remodelling. In parallel, this thesis examines whether the paralog citrin also regulates Opa1-mediated cristae maintenance.