Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb⁺, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.