Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate

Uncoupling proteins (UCPs) are a subfamily of the mitochondrial carrier family SLC25. In Drosophila melanogaster four UCPs, named DmUCP4A-C and DmUCP5, were identified on the basis of their sequence homology with mammalian UCP4 and UCP5.1 In Parkinson’s disease models, DmUCP4A exerted a protective role against mitochondrial dysfunction, by increasing mitochondrial membrane potential and ATP synthesis.2 To date, the biochemical function of DmUCP4A needs to be investigated, although its possible involvement in mitochondrial uncoupling has been ruled out. We show that DmUCP4A expressed in bacteria and reconstituted in phospholipid vesicles catalyzes a saturable unidirectional transport of aspartate, inhibited by typical mitochondrial carrier inhibitors. Swelling experiments led in yeast mitochondria have demonstrated that this transport is not proton-coupled. The biochemical function of DmUCP4A has been further confirmed in a yeast cell model, in which growth has required an efflux of aspartate from mitochondria. Notably, DmUCP4A is the first UCP4 homolog from any species to be biochemically characterized. In D. melanogaster, DmUCP4A could be involved in the transport of aspartate from mitochondria to the cytosol, in which it could be used for protein and nucleotide synthesis, as well as in the biosynthesis of ß-alanine and N-acetylaspartate (a precursor of myelin biosynthesis), which play key roles in signal transmission in the central nervous system.