Abstract
Purpose :
Though raised intraocular pressure (IOP) is the main risk factor, about a third of patients with glaucoma have IOP within the normal range (Normal Tension Glaucoma - NTG). Whilst reducing IOP can slow progression, glaucoma may deteriorate despite IOP lowering, suggesting that other factors confer susceptibility. Mitochondrial dysfunction is an important factor contributing to a number of age-related neurodegenerative diseases and mounting evidence suggests that it contributes to glaucoma pathogenesis. Nicotinamide adenine dinucleotide (NAD+) is a central coenzyme involved in mitochondrial function and fundamental biological processes in health, ageing and disease. NAD+ depletion has been observed in other neurodegenerations
Methods :
NAD+ and NADH levels (Promega NAD/NADH-Glo™ Assay; two technical repeats) and mitochondrial function (XFe24 Analyzer), expressed as oxygen consumption rate (OCR) pmol/min, were measured in the same fibroblast lines from 5 NTG patients and 5 non-glaucomatous Controls. NAD+ and NADH concentrations were normalised to protein content and expressed as nM/μg. NTG inclusion criteria: minimum 5 years follow up with at least 8 reliable visual fields, IOP≤ 21mmHg. Controls were age matched with an absence of glaucoma and IOP ≤ 21mmHg. Both groups had absence of active haematological malignancy/recent infection/chemotherapy/radiotherapy or drugs known to affect mitochondrial function
Results :
Median (IQR) NAD+ (p<0.01) and NADH+ (p<0.05) concentrations (average of two runs) were significantly reduced in the NTG group: 374 (372 - 400), 56 (42 - 57), compared to the Control group: 656 (613 - 1164), 121 (80 - 171) respectively (Fig. B, D). Median Basal (p<0.01), ATP-linked (p<0.01), and Maximal Respiration (p<0.05), were significantly lower in the NTG group compared to the Control group (Fig. A, C, D). The estimation of NAD+ concentration was relatively imprecise with a mean difference of 29% and SD of differences of 19% between the two runs
Conclusions :
Our data show evidence of relative NAD+ and NADH depletion in NTG patients, which may contribute to a reduction of various components of systemic mitochondrial function, supporting NAD+ levels as a potential therapeutic target
This is a 2021 ARVO Annual Meeting abstract.