RPE Lactate Transporters: A Role in Retinal Survival

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DESCRIPTION (provided by applicant): The retinal pigment epithelium (RPE) is the gatekeeper of the outer retina and controls the movement of ions, metabolites, and fluid between the outer retina and the choroidal blood supply. The energy demands of phototransduction are met through glucose metabolism via glycolytic and oxidative pathways. The neural retina is one of the most metabolically active tissues in the body and produces large quantities of lactate via aerobic glycolysis and CO2 via respiration. Because photoreceptor cell function is dependent on strict pH regulation, it is essential that lactate be removed from the subretinal space (SRS). Our studies have shown that the RPE expresses two proton-coupled monocarboxylate transporters that facilitate the trans-epithelial movement of lactate from the subretinal space to the choroid; MCT1 in the apical membrane and MCT3 in the basolateral membrane. Both transporters are linked to CD147, an accessory protein required for proper trafficking to the plasma membrane. Mice with targeted deletion of the gene encoding CD147 (Bsg) have reduced visual function and retinal integrity due to a loss of expression of MCT1, MCT3, and MCT4 in the retina. Loss of these transporters inhibits glycolysis and disrupts pH homeostasis accounting for the reduced electroretinograms (ERGs) and photoreceptor cell death. In the Mct3-/- mouse, while the phenotype is less severe than that of the Bsg-/- mouse, increased retinal lactate levels and reduced light-stimulated photoreceptor responses are observed. Overall, these findings demonstrate that MCTs play an essential role in maintaining visual function by regulating the pH and the osmolarity of the SRS. Therefore, we propose: 1) To test the hypothesis that MCTs contribute to metabolic and pH homeostasis of the outer retina, 2) To test the hypothesis that bicarbonate transporters enhance trans-epithelial lactate transport in the RPE, 3) To test the hypothesis that C-terminal cytoplasmic tails of MCTs have binding motifs that orchestrate their assembly into macromolecular complexes and stabilize their polarized distribution, stability and transporter activity. The results of these studies will elucidate the molecular mechanisms that regulate the expression, polarized trafficking and coordinated activities of metabolic transporters in the RPE. These findings should further our understanding of the multifaceted roles that metabolic transporters play in maintaining normal visual function and how changes in expression or activity of these transporters could lead to degenerative abnormalities in the eye. PUBLIC HEALTH RELEVANCE: The retina has an extremely high rate of metabolism and produces large quantities of lactate. Since acidic pH inhibits the ability of photoreceptor cells to respond to light, lactate must be transported out of the retina to maintain normal visual function. The retinal pigment epithelium forms the outer blood-retinal barrier and performs many essential functions for the retina. One of these is to transport lactate, protons and water out of the retina to be removed by the choroidal blood vessels. Previous studies from our laboratory have identified two lactate transporters in the RPE that are likely to control lactate movement out of the retina. The purpose of the current studies is to understand how the functional activity of these transporters is regulated since failure to efficiently remove lactate from the retina leads to degeneration of the visual cells and blindness.