Open AccessDisturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
Author(s) -
Jeffrey M. Harder,
Chelsea Guymer,
John Wood,
Evangelia Daskalaki,
Glyn Chidlow,
Chi Zhang,
Revathi Balasubramanian,
Brynn H Cardozo,
Nicole E. Foxworth,
Kelly E Deering,
Tionna B Ouellette,
Christa Montgomery,
Craig E. Wheelock,
Robert J. Casson,
Pete A. Williams,
Simon W. M. John
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2014213117
Subject(s) - neurodegeneration , neuroprotection , biology , neuroscience , pi3k/akt/mtor pathway , pyruvate dehydrogenase complex , bioenergetics , medicine , disease , microbiology and biotechnology , mitochondrion , biochemistry , signal transduction , enzyme
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.