Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin

Abstract

Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.

AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma

“…These data identify AMPK as a critical regulator of mTORC1-mediated maintenance of synaptic connections in energetically stressed neurons. Our results contrast with previous findings showing that the mTOR inhibitor rapamycin promoted RGC survival [ 63 ]. Rapamycin has been shown to have both beneficial and detrimental effects on metabolism, a disparity that has been largely attributed to non-specific effects depending on the time-course of administration [ 64 , 65 ].…”

Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies

“…B2 mice treated with either vitamin B3 rich diet or gene therapy driving Nmnat1, a key NAD+-producing enzyme, did not develop glaucoma despite IOP elevation [10]. Similar results have been obtained with a diet enriched with pyruvate, which provides bioenergetic support [57]. Age-related factors also alter eye structure independently of IOP [58,59] (Figure 6B-D).…”

Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies

“…B2 mice treated with either vitamin B3 rich diet or gene therapy driving Nmnat1, a key NAD+-producing enzyme, did not develop glaucoma despite IOP elevation [10]. Similar results have been obtained with a diet enriched with pyruvate, which provides bioenergetic support [56]. Age-related factors also alter eye structure independently of IOP [57,58] (Figure 5 B,C,D).…”