Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
| Autor: | Glyn Chidlow, Simon W. M. John, Jeffrey M. Harder, Evangelia Daskalaki, Peter A. Williams, Nicole E. Foxworth, Craig E. Wheelock, Tionna B Ouellette, Robert J Casson, Chelsea Guymer, John P. M. Wood, Chi Zhang, Brynn H Cardozo, Christa Montgomery, Kelly E Deering, Revathi Balasubramanian |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
genetic structures pyruvate Glaucoma Carbohydrate metabolism Neuroprotection Retina Rats Sprague-Dawley chemistry.chemical_compound Internal medicine Pyruvic Acid medicine Animals Glycolysis retinal ganglion cell PI3K/AKT/mTOR pathway Intraocular Pressure Sirolimus Multidisciplinary Glycogen business.industry TOR Serine-Threonine Kinases Neurodegeneration Metabolism Biological Sciences medicine.disease eye diseases neuronal metabolism Mice Inbred C57BL Disease Models Animal Endocrinology Glucose Neuroprotective Agents chemistry Mice Inbred DBA Nerve Degeneration sense organs business Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure during glaucoma pathogenesis. This paper addresses these relationships and provides a deeper understanding of this common neurodegeneration. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism, and detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Supporting this, oral supplementation of pyruvate or mTOR inhibition by rapamycin strongly protects from neurodegeneration. Bioenergetic enhancement thus provides a readily clinically translatable strategy for neurodegenerative disease. This study provides important avenues for neuroprotection against glaucoma by targeting key metabolic pathways that may be mirrored in other neurodegenerative diseases in which metabolic dysregulation may play a key role. 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. |
| Databáze: | OpenAIRE |
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