Mitochondrial function – a potentially modifiable risk factor for glaucoma?

The role of mitochondrial function as a potentially modifiable risk factor for glaucoma was the focus of this year’s Mooney Lecture at the Irish College of Ophthalmologists 2023 Annual Conference, which was delivered by an eminent UK researcher and innovator in the field of glaucoma.

Prof David Garway-Heath, Consultant Ophthalmic Surgeon at Moorfields Eye Hospital, London, and Glaucoma UK Professor of Ophthalmology for Glaucoma and Allied Studies at the Institute of Ophthalmology, University College London, UK, was the principal investigator of the UK Glaucoma Treatment Study. This was a landmark trial in glaucoma management and the first trial in glaucoma to be published in The Lancet. 

His talk in Killarney was a fascinating examination of the role of mitochondrial function as a risk factor in the development of glaucoma, and ongoing work, including his own substantial research, in the area and efforts to trial a potential intervention.

Glaucoma is the leading cause of irreversible blindness worldwide, and the key risk factor is high levels of intraocular pressure (IOP) and older age. IOP reduction is currently the only proven method shown to slow glaucoma development/progression. However, a significant subset of patients (15-to-20 per cent) still lose vision despite best treatment, suggesting that other factors confer susceptibility, Prof Garway-Heath told delegates in Killarney.

Mitochondrial dysfunction has been implicated in the pathophysiology of a number of neurodegenerative diseases, and has now been shown to play a role in the pathogenesis of glaucoma. Retinal ganglion cells (RGC), because of their high energy requirement, are heavily dependent on mitochondria for survival and function. Several studies of glaucoma patients have shown higher levels of mitochondrial dysfunction in their RGC, thus indicating that “mitochondrial function is an important risk factor [in glaucoma] that is possibly modifiable,” he noted.

“So what we have so far is that mitochondrial function is implicated in glaucoma by genetic evidence, experimental evidence, and clinical evidence.”

So can prevention of mitochondrial dysfunction reduce the risk of glaucoma, and improve vision in glaucoma patients? During the Mooney Lecture, Prof Garway-Heath presented his laboratory and pre-clinical work which looked at the impact of nicotinamide in preventing mitochondrial dysfunction, thus protecting RGC and potentially preventing/treating glaucoma. Nicotinamide is a water-soluble form of vitamin B3/niacin, which replenishes molecules important for the functioning of mitochondria, and a French study found nicotinamide levels to be lower in glaucoma patients compared to controls.

“Nicotinamide is cheap, safe and well tolerated, but we are not encouraging people to use vitamin B3 yet as we need the evidence that it is effective, before we can recommend it, but it is looking like a good candidate treatment,” he told the Medical Independent.

The results to date “look very promising indeed”, with big effects in those [lab and animal] models, he said.

“Then there is the short-term trial looking at improvement in vision in glaucoma patients on nicotinamide, and that also seems to show some activity… but that doesn’t necessarily tell us it is going to affect the long-term [disease] course and that is what the next trial is about, to look at affecting the long-term course of the disease,” Prof Garway-Heath said.

His research is also trying to identify biomarkers to determine who would benefit from taking nicotinamide.

He hopes that one day it could be as simple as those at risk of glaucoma just having to take a blood test. “We’re heading towards a stratified medicine approach. Glaucoma is multifactorial. Mitochondrial function won’t underlie glaucoma in everybody, but I believe there will be a substantial subset of the glaucoma population where it is important and this sort of intervention would be important.”