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.
Recommended Citation
Harder JM,
Guymer C,
Wood J,
Daskalaki E,
Chidlow G,
Zhang C,
Balasubramanian R,
Cardozo B,
Foxworth N,
Deering K,
Ouellette T,
Montgomery C,
Wheelock C,
Casson R,
Williams P,
John S.
Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin. Proc Natl Acad Sci U S A 2020 Dec 29; 117(52):33619-33627
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.