MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Glaucoma Models




Inman, Denise
Pappenhagen, Nathaniel
Harun-Or-Rashid, Mohammad
Jassim Jaboori, Assraa


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Purpose: The ketogenic diet decreases retinal ganglion cell degeneration in models of glaucoma. Retina and optic nerves from mice on the diet also had elevated expression of monocarboxylate transporter 2 (MCT2), which transports monocarboxylates intracellularly to be used as fuel for mitochondria. We used a viral vector approach to increase expression of MCT2 in retinal ganglion cells (RGCs) to determine if the upregulation of MCT2 without the ketogenic diet could increase RGC survival in glaucoma. Methods: We injected AAV2-CAG2-mSLC16A7-2A-GFP (AAV2:MCT2) intraocularly to infect RGCs and promote MCT2 overexpression in the DBA/2J mouse model of glaucoma and the magnetic microbead induced ocular hypertension (OHT). Retinas and optic nerves were collected; axons were stained with PPD, and RGCs were labeled with RBPMS for counting. Data was compared to DBA/2J-Gpnmb+/+ or sham injected controls. Metabolic proteins of interest were quantified using capillary electrophoresis, and visual function was tested with pattern ERG (PERG). Results: AAV2:MCT2 injection rescued RGCs in both models of glaucoma. Glaucomic mice injected with AAV2:MCT2 had significantly higher axon counts, RGC soma densities, and visual function than glaucomic mice treated with a control virus (AAV2:eGFP). The decreased pAMPK/AMPK ratio indicated that AAV2:MCT2 treated eyes were under less metabolic stress than eyes treated with AAV2:eGFP. PERG traces showed higher P1 amplitude in mice treated with AAV2:MCT2 than in controls, indicating improved visual function in those mice. Conclusions: MCT2 overexpression caused increased RGC survival in two models of glaucoma, suggesting there is a metabolic problem underlying glaucomic degeneration.