Higher Reliance on Glycolysis Limits Glycolytic Responsiveness in Degenerating Glaucomatous Optic Nerve

Jassim, Assraa Hassan; Coughlin, Lucy; Harun‐Or‐Rashid, Mohammad; Kang, Patrick T.; Chen, Yeong Renn; Inman, Denise M.

doi:10.1007/s12035-019-1576-4

Cited by 31 publications

(28 citation statements)

References 43 publications

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“…As NAD is a critical factor for glycolysis, together a decrease in NAD and pyruvate, and increase in glucose, are consistent with a glycolytic deficiency. During D2 glaucoma, RGC axons were recently shown to have reduced capacity to increase glycolysis in response to metabolic demand (21). Although the regulation of glycolysis is complex, glycolytic insufficiency can occur if NAD levels decrease as the reduction of NAD + to NADH is essential for conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate.…”

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confidence: 99%

“…mTOR is a master regulator of metabolism, and mTOR complex 1 (mTORC1) modulates glucose use and glycolysis through Hif1α (23). Hif1α is increased in the retinas of D2 mice following high IOP (10) and D2 optic nerves have a decreased maximal respiratory rate and altered glycolytic responses (21). Analysis of retinal proteins by an mTOR pathway antibody array demonstrated a specific increase in phospho-S6 and phospho-S6K, classic indicators of mTOR activation (Fig 3C).…”

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Oral pyruvate prevents glaucomatous neurodegeneration

Williams

Harder

Guymer

et al. 2020

Preprint

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Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that agerelated bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.

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Oral pyruvate prevents glaucomatous neurodegeneration

Williams

Harder

Guymer

et al. 2020

Preprint

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“…For the D2, it may be the case that the improvement in energy homeostasis (evident with the decline in pAMPK/AMPK ratio) enabled improved function for all modes of ATP generation, glycolysis and oxidative phosphorylation. Another possibility is that the D2 ON, relying heavily on glycolysis as we have demonstrated in prior studies (Jassim et al, 2019), would not have experienced an increase in monocarboxylate import through MCT2 sufficient enough to displace the energy that could be obtained through glycolysis. Important to note is that the observed changes in hexokinase activity are relative; the hexokinase activity in the D2 ON with AAV2:MCT2, despite being significantly higher than untreated D2, was still lower than the control ON in the OHT experiment.…”

Section: Discussionmentioning

confidence: 96%

“…MCT2 fl/+ mice injected with AAV2-cre had their optic nerves removed and prepped for analysis in the Seahorse XF24 Analyzer as described (Jassim et al, 2019). The optic nerves were secured in an Islet capture microplate, within a plasma-thrombin clot, with DMEM (10mM glucose, 0.5mM sodium pyruvate, 4mM glutamine) as media.…”

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MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma

Harun‐Or‐Rashid

Pappenhagen

Zubricky

et al. 2020

Preprint

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Highlights:• Loss of MCT2 in retina compromises visual function and ATP production in optic nerve • MCT2 overexpression preserves RGC soma and axon number in two glaucoma models • MCT2 overexpression improves energy homeostasis in optic nerve AbstractImproving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2 fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.

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Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

et al. 2022

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IMPORTANCE Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting.OBJECTIVE To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.DESIGN, SETTING, AND PARTICIPANTS In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021.INTERVENTIONS Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization). MAIN OUTCOMES AND MEASURESNumber of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]).RESULTS Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, −0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs −0.002 dB per week; 95% CI, −0.27 to 0.09; P = .35) or VFI (0.09 vs −0.02% per week; 95% CI, −0.53 to 0.36; P = .71). CONCLUSIONS AND RELEVANCEA combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

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Higher Reliance on Glycolysis Limits Glycolytic Responsiveness in Degenerating Glaucomatous Optic Nerve

Cited by 31 publications

References 43 publications

Oral pyruvate prevents glaucomatous neurodegeneration

Oral pyruvate prevents glaucomatous neurodegeneration

MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

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