Lactate transporters are essential for maintain function in rod but not cone photoreceptor cells.

Abstract

Purpose : Glucose transported into the outer retina is metabolized primarily through aerobic glycolysis generating large amounts of lactate. Transport of lactate within and out the retina is facilitated by proton-coupled monocarboxylate transporters (MCTs), that require an accessory protein Bsg for proper trafficking to the plasma membrane. Mice with a global knockout of Bsg have severely reduced photopic and scotopic ERGs and a loss of MCTs in the RPE and neural retina. Since there is some controversy in the literature about whether photoreceptor cells produce or oxidize lactate, we generated transgenic mouse lines with Bsg^-/- knocked out of rod (RPC) or cone photoreceptors (CPC) to address this issue.

Methods : Mice carrying floxed alleles for Bsg (Bsg^Flox/Flox) were crossed with Cre transgenic lines that target cone (ConeΔBsg) or rods (RodΔBsg). Retinal structure and function were assessed over time in Bsg^Flox/Flox Cre transgenic mice and control littermates by spectral-domain optical coherence tomography (SD-OCT) and electroretinograms (ERGs). Metabolomics and biochemical techniques were used to determine the metabolic changes of the retina in RodΔBsg mice. Histological and immunofluorescence (IF) confocal microcopy were used to assess changes in retinal structure and protein expression.

Results : ERGs were recorded from RodΔBsg, ConeΔBsg, and age match control mice over a period of 1 month to 8 months of age. RodΔBsg mice developed a progressive loss of rod function beginning at 2 months of age which was correlated with thinning of the ONL observed by SD-OCT. Cone function was largely spared in RodΔBsg mice. In comparison, ConeΔBsg ERGs were comparable to control mice at 2 months of age and at later ages, we noted a modest decrease in cone function that was not correlated with cone cell death. GC/MS analysis of metabolites from freshly isolated control and RodΔBsg retinas showed an increase in overall levels of lactate, suggesting export of lactate was inhibited in RPC. Retinas isolated from control and RodΔBsg mice were incubated in [U-¹³C] lactate to determine if there were changes in lactate uptake. We found that there was a decrease in in [U-¹³C] lactate levels in the RodΔBsg retinas compared to controls as well as a reduction in labeled TCA intermediates.

Conclusions : RPC both produce and utilize lactate while CPC do not seem to rely on lactate transporters to maintain metabolic homeostasis.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.