REP-1 depletion causes altered mitochondrial energy metabolism in CHM disease, shifting from glycolysis to lipid oxidation

The persistent supply of glucose in the retina is essential for underpinning ATP production to meet the retinal cell’s energy requirements essential for the vision. Glucose transporters mainly mediate the glucose supply and diffusion thorough the retinal vasculature, choroid/RPE and photoreceptor cells. While the physiological mechanisms behind glucose supply have been well studied and described, how glucose supply dysfunction contributes to the phenotype of retinal disease is poorly understood. Now we provide evidence that retinal energetic failure dependent by glucose supply defect explains large part of the phenotype of Choroideremia (CHM), an X-linked chorioretinal dystrophy caused by mutations in the Rab escort protein-1 (REP-1) gene. By interrogating the effect of REP-1 depletion in CHM, we found that alteration of glucose transporters GLUT-4 and GLUT-1 in the RPE/retina cells contribute to the CHM phenotype. REP-1 loss induces glucose-dependent bioenergetic deficiency, altering mitochondria morphology and function. By restoring both GLUTs expression and membrane translocation through pharmacological induction of phosphatidylinositol 3-Kinase pathway, we re-established the glucose uptake and its commitment towards RPE/retina both in vitro and in vivo. This study supports the notion that, in CHM, the absence of REP-1 causes an altered glucose uptake, which determines a deficit of energy compromising retinal cell homeostasis and function.