Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice

Abstract

To meet the high-energy demands of photoreceptor cells, the outer retina metabolizes glucose through glycolytic and oxidative pathways, resulting in large-scale production of lactate and CO2. Mct3, a protoncoupled monocarboxylate transporter, is critically positioned to facilitate transport of lactate and H ϩ out of the retina and could therefore play a role in pH and ion homeostasis of the outer retina. Mct3 is preferentially expressed in the basolateral membrane of the retinal pigment epithelium and forms a heteromeric complex with the accessory protein CD147. To examine the physiological role of Mct3 in the retina, we generated mice with a targeted deletion in Mct3 (slc16A8). The overall retinal histology of 4-to 36-wk-old Mct3Ϫ/Ϫ mice appeared normal. In the absence of Mct3, expression of CD147 was lost from the basolateral but not apical RPE. The saturated a-wave amplitude (amax) of the scotopic electroretinogram (ERG) was reduced by approximately twofold in Mct3 Ϫ/Ϫ mice relative to wildtype mice. A fourfold increase in lactate in the retina suggested a decrease in outer-retinal pH. In single-cell recordings from superfused retinal slices, saturating amplitudes of single rod photocurrents (Jmax) were comparable indicating that Mct3 Ϫ/Ϫ mouse photoreceptor cells were inherently healthy. Based on these data, we hypothesize that disruption of Mct3 leads to a potentially reversible decrease in subretinal space pH, thereby reducing the magnitude of the light suppressible photoreceptor current. monocarboxylate transporter 3; lactate transport; retinal pigment epithleium; pH regulation; photoreceptor; electroretinogram THE RETINAL PIGMENT EPITHELIUM (RPE) forms the outer-blood retinal barrier and performs many functions essential for maintaining the health and functional activity of photoreceptors. Interposed between the choroidal vessels and the photoreceptor cells, the RPE regulates the transport of glucose to the avascular outer retina. Eighty percent of the glucose transported into the outer retina is metabolized via glycolysis producing large amounts of lactate both in the light and the dark (41,42,44). Lactate produced by glycolysis in Müller glia is then used to fuel oxidative phosphorylation in photoreceptor cells (35). The transfer of lactate from glia to neurons is facilitated by proton-coupled monocarboxylate transporters and has been referred to as the "lactate shuttle" (27). Inhibition of monocarboxylate transport or glycolysis results in attenuation of light-

Interaction of monocarboxylate transporter 4 with β1-integrin and its role in cell migration

“…In support of this hypothesis, previous work from our lab demonstrated that MCT1 and MCT3, the isoforms expressed in RPE in vivo, were not expressed in the RPE of CD147-knockout mice (36). Similar results were observed in MCT3-knockout mice (12). In vitro, we found that silencing MCT4 in the breast cancer cell line, MDA-MB-231, resulted in retention of CD147 in the endoplasmic reticulum (19).…”

Loss of Caveolin-1 Impairs Retinal Function Due to Disturbance of Subretinal Microenvironment

“…Genetic ablation of the basolateral lactate transporter of the RPE, monocarboxylate transporter 3 (Mct3; slc16A8), leads to a strikingly similar ERG impairment as that found in this study, in vivo, and also does not affect responses recorded from isolated rods (79). Loss of Mct3 leads to extracellular accumulation of lactate and probably decreases subretinal pH.…”

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

“…Among these targets, several were noted as important developmental regulators (Meis2) (Conte et al, 2010;Xu et al, 2002) as well as encoding proteins involved in RPE physiology, such as Slc16a8 (Adijanto et al, 2012). Slc16a8 is a member of a family of proton- coupled monocarboxylate transporters that mediate lactate transport across the cell membrane, and Slc16a8 is highly expressed in the RPE, required for visual function and associated with AMD (Daniele et al, 2008;Philp et al, 1998;Priya et al, 2012), and has been experimentally shown to be upregulated by miR-204 (Adijanto et al, 2012). Genes with as yet unknown functions in the RPE, such as Ap1s3, which encodes a subunit of adaptor protein complex, should also be considered when attempting to identify the underlying cause of the phenotype following miRNAs loss from the RPE, as this subunit was recently shown to play a role in the endosomal translocation of signaling components involved in inflammation in skin keratinocytes (Boehm and Bonifacino, 2002;Setta-Kaffetzi et al, 2014).…”