Retinal Ganglion Cell Bioenergetics: NAD⁺ Flux and the Foveal Mitochondrial Load
Abstract
A structured synthesis of the published literature on energy demand in the foveal cone and retinal ganglion cell (RGC) axis, the role of the NAD⁺/NADH redox pair, and reported RGC protection following NAD⁺ repletion in optic-neuropathy and glaucoma models. Presented as a neutral reference survey; no human outcome or product effect is asserted.
Methods
- 01Scope : RGC and photoreceptor mitochondrial bioenergetics
- 02Sources : peer-reviewed primary studies and reviews (in-vitro, animal)
- 03Extraction : reported NAD⁺ dependence, sirtuin/PARP involvement
- 04Framing : observational synthesis, no meta-analysis of human endpoints
Literature Synthesis
Why These Neurons Run Close to the Line
Retinal ganglion cells (RGCs) are structurally unusual among central-nervous-system neurons. Their axons cross the inner surface of the retina unmyelinated, because myelin in the light path would scatter the image, and only acquire a myelin sheath after passing through the lamina cribrosa. Conduction along unmyelinated axon is substantially more expensive per action potential than saltatory conduction, and the unmyelinated segment is correspondingly dense with mitochondria [1]. The result is a projection neuron operating with little metabolic reserve as a matter of normal function rather than pathology. Reviews of RGC bioenergetics treat this narrow margin as the reason the cell type is disproportionately represented in age-related and pressure-related optic neuropathy [1,2].
The NAD⁺ Decline, and What Reversing It Did in Mice
The most-cited experimental result in this area is Williams and colleagues in Science (2017) [3]. Working in the DBA/2J mouse, a strain that develops age-related ocular hypertension and glaucoma, the group reported that retinal NAD⁺ falls with age and that mitochondrial abnormalities in RGCs appear before any detectable degeneration. The bioenergetic deficit precedes the cell loss rather than following it. Oral nicotinamide, a precursor cells convert into NAD⁺ through the salvage pathway, was protective both prophylactically and when started after disease onset, as was Nmnat1 gene therapy. At the highest exposure tested, 93% of eyes did not develop glaucoma. The distinction matters for reading the rest of this literature: the intervention studied is a precursor, not NAD⁺ itself, and the two are different molecules with different pharmacokinetics.
The Move Into Humans Is More Equivocal
Two randomised trials have carried the question into patients. Hui and colleagues ran a crossover, double-masked trial in 57 people with treated primary glaucoma and reported an improvement in inner-retinal function measured by the photopic negative response. PhNR Vmax rose 14.8% (95% CI 2.8 to 26.9, p=0.02) on nicotinamide, against 5.2% on placebo, which did not reach significance; 23% of participants exceeded the 95% coefficient of repeatability versus 9% on placebo [4]. Note the shape of that result: it is a within-arm improvement alongside a non-significant placebo arm, not a 14.8% difference between groups. Dosing ran 6 weeks at 1.5 g/day then 6 weeks at 3.0 g/day, and the crossover was performed without a washout period. A trend toward improved visual-field mean deviation was also reported. De Moraes and colleagues subsequently ran a Phase 2 trial of nicotinamide (1000-3000 mg) with pyruvate (1500-3000 mg) in open-angle glaucoma [5]: 42 randomised, 32 completing, median follow-up 2.2 months, with more visual-field locations improving beyond normal variability on treatment than placebo (median 15 against 7, p=0.005) and no serious adverse events. Both trials enrolled patients already on intraocular-pressure-lowering therapy, so this is an add-on question and never a replacement one. Both measured electrophysiological or perimetric endpoints rather than long-term structural preservation, and both were small and short.
Where the Professional Bodies Currently Stand
In 2025 the American Glaucoma Society and the American Academy of Ophthalmology issued a joint position statement on nicotinamide for glaucoma neuroprotection [6]. Two sentences from it carry the weight. On the evidence: these studies' endpoints “include functional findings detectable in a research setting, but do not consistently translate to visual recovery that is impactful to the patient.” And on practice: “the use of nicotinamide at high doses (≥ 3 grams/day) is not recommended outside the confines of clinical trials.” They add that nicotinamide is not approved for glaucoma, that its safety at these doses is unknown, and that trial use is accompanied by hepatic monitoring. That is the honest state of the field. The animal evidence is strong and mechanistically coherent; the human evidence is early, small, and measured on surrogate endpoints; and the bodies that write the guidance have not moved. Anyone reading this note as a reason to act on their own eyes should read the position statement instead, and talk to an ophthalmologist.
Documented References
- [1]
Williams PA, Harder JM, John SWM. (2017) Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma.
Journal of Glaucoma 26(12):1161-1168
View on PubMed - [2]
Casson RJ, Chidlow G, Crowston JG, Williams PA, Wood JPM. (2021) Retinal energy metabolism in health and glaucoma.
Progress in Retinal and Eye Research 80:100881
View on PubMed - [3]
Williams PA, Harder JM, Foxworth NE, et al. (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.
Science 355(6326):756-760
View on PubMed - [4]
Hui F, Tang J, Williams PA, et al. (2020) Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: a crossover randomized clinical trial.
Clinical & Experimental Ophthalmology
View on PubMed - [5]
De Moraes CG, John SWM, Williams PA, et al. (2022) Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial.
JAMA Ophthalmology
View on PubMed - [6]
American Glaucoma Society; American Academy of Ophthalmology. (2025) Position Statement on Nicotinamide Use for Glaucoma Neuroprotection.
Ophthalmology Glaucoma
View on PubMed
References point to published, third-party scientific literature, provided for research context. Citation of a study is not an endorsement of any use of this material.
DISCLOSURE : This report presents anonymized in-silico and/or observational reference data. It does not establish a causal relationship between any catalogued material and any physiological outcome, and it is not a claim of safety, efficacy, or benefit.
Compounds referenced
This note surveys published work on the following compound. They are research materials, not treatments, and nothing here indicates they are suitable for any use in humans.