Title

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

Document Type

Article

Publication Date

12-29-2020

Keywords

JMG

JAX Source

Proc Natl Acad Sci U S A 2020 Dec 29; 117(52):33619-33627

Volume

117

Issue

52

First Page

33619

Last Page

33627

ISSN

1091-6490

PMID

33318177

DOI

https://doi.org/10.1073/pnas.2014213117

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.

Comments

We thank Mimi de Vries and Amy Bell for assistance with organizing mouse colonies and intraocular pressure measurements; and the staff of the histology, gene expression services, and computational sciences at The Jackson Laboratory and Columbia University, including John Peregrin.

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