Compensatory transporter upregulation facilitates retinal ganglion cell survival in glaucoma after MCT2 elimination.

Metabolic dysfunction contributes to glaucoma progression, including through substrate availability and the presence and concentration of substrate transporters. Observations of metabolic substrate transporter loss in glaucoma, including loss of monocarboxylate transporter-2 (MCT2), have suggested there are serious implications for metabolic dysfunction on the health and survival of retinal ganglion cells (RGCs). In this study, we investigate whether MCT2 is necessary and sufficient for RGC survival in vivo and after ocular hypertension (OHT). We used an inducible conditional knockout (KO) mouse to remove MCT2 in Thy1-positive RGCs, then assessed RGC survival and function after OHT. MCT2 KO alone did not affect RGC density but did significantly reduce pattern electroretinogram amplitude. Upregulation of MCT1, MCT4, and GLUT3 transporters occurred as a result of MCT2 KO, suggesting that RGCs employ compensatory measures to meet their metabolic needs. Introducing oral nicotinamide (500 mg/kg/day) to test its ability to offset potential energy substrate insufficiency from MCT2 KO showed that nicotinamide was protective of RGC density for the MCT KO group but did not preserve RGC density or function for MCT2 KO + OHT. These data indicate RGCs are able to undergo compensatory adaptation to MCT2 KO with substrate transporter upregulation, which preserves their density but is not sufficient to fully preserve their function. Intervention that supplies metabolic intermediates can mitigate the loss of MCT2.