Photobiomodulation in Age-Related Macular Degeneration: A Mitochondrial Bioenergetic Framework and Translational Perspective

For Full access to the study, click on the link below:

https://www.mdpi.com/2075-1729/16/7/1098

 

 

Paper summary

Desmettre T, Mordon S. “Photobiomodulation in Age-Related Macular Degeneration: A Mitochondrial Bioenergetic Framework and Translational Perspective.” This is a targeted narrative review and conceptual paper, not a new clinical trial. Its central argument is that photobiomodulation’s effects in AMD may be understood through the interaction of light dose and the remaining mitochondrial functional reserve of retinal cells.

Central thesis

The authors propose that PBM is most likely to produce a biological response when two conditions are met:

1. The light exposure falls within an optimal bioenergetic window.
   Too little stimulation may be ineffective, while excessive stimulation may produce a weaker or suboptimal response—a biphasic or bell-shaped dose-response relationship.
2. The retina retains enough viable mitochondrial function to respond.
   Eyes with early or intermediate AMD may still contain metabolically impaired but recoverable photoreceptors and RPE cells. In advanced geographic atrophy, extensive cellular loss and severe mitochondrial dysfunction may leave little tissue available for “metabolic rescue.”

The diagram on page 8, Figure 4 illustrates the dose-dependent window. Figure 5 on page 10 illustrates the proposed decline in responsiveness as AMD advances.

Why mitochondria matter in AMD

The retina is exceptionally energy demanding:

• Photoreceptors require large quantities of ATP for phototransduction and maintenance of ionic gradients.
• RPE cells depend on mitochondrial oxidative phosphorylation for outer-segment phagocytosis, retinoid recycling and other homeostatic functions.
• Aging and AMD are associated with mitochondrial DNA damage, impaired respiratory-chain activity, altered mitochondrial structure, oxidative stress and declining cellular resilience.

The authors therefore consider the photoreceptor–RPE complex particularly vulnerable to declining mitochondrial efficiency—and potentially responsive to treatments that modulate bioenergetics.

Proposed PBM mechanisms

The paper reviews several overlapping mechanisms rather than identifying one proven pathway:

• Cytochrome-c oxidase modulation: red or near-infrared photons may interact with complex IV of the respiratory chain.
• Nitric oxide photodissociation: light may release inhibitory nitric oxide from respiratory-chain components, potentially improving electron transport.
• Changes in mitochondrial respiration and ATP production.
• Redox signalling: transient reactive-oxygen-species changes may activate adaptive pathways such as Nrf2 and PGC-1α.
• Possible anti-inflammatory and mitochondrial-biogenesis effects.
• Thermal microenvironment hypothesis: active mitochondria may have subtle local physicochemical or thermal conditions that affect respiration.

The authors grade cytochrome-c-oxidase activation and nitric-oxide photodissociation as having the strongest experimental support. Increased ATP production and redox signalling have moderate support; anti-inflammatory effects are less established; and the mitochondrial thermal hypothesis remains theoretical and debated.

Importantly, the thermal concept should not be interpreted as established heating of the retina. The paper acknowledges substantial methodological and theoretical objections to large intracellular mitochondrial temperature gradients.

Clinical evidence reviewed

The clinical literature is described as encouraging but heterogeneous.

 

Across the literature, the most consistent findings concern functional measures, such as:

• Best-corrected visual acuity
• Low-luminance visual acuity
• Contrast sensitivity
• Retinal sensitivity

Evidence for genuine disease modification—such as sustained drusen reduction, slower geographic-atrophy growth or prevention of conversion to neovascular AMD—is considerably weaker and less consistently studied.

Proposed stage-dependent response

The clinical-translation table on page 12 summarizes the authors’ model:

• Early AMD: mild mitochondrial dysfunction, relatively high potential responsiveness and possible improvement in bioenergetics.
• Intermediate AMD: moderate dysfunction, variable or moderate responsiveness and partial functional improvement.
• Advanced geographic atrophy: severe dysfunction, low or absent responsiveness and minimal expected functional effect.

This is presented as a conceptual prediction, not as a validated treatment-selection algorithm.

Potential biomarkers

Because mitochondrial reserve cannot currently be measured directly in the clinic, the authors propose possible surrogate markers:

• Ellipsoid-zone integrity
• Preserved photoreceptor structure
• Hyperreflective foci
• Transdifferentiated RPE cells
• Drusen phenotype
• Subretinal drusenoid deposits
• Retinal sensitivity
• Dark adaptation

These could eventually help identify responders, but they have not yet been validated as PBM-selection biomarkers.

Major limitations

The paper is appropriately cautious:

• It is a selected narrative review, not a systematic review or meta-analysis. Studies were chosen to develop the proposed mechanistic framework.
• Much of the positive clinical evidence comes from industry-sponsored studies using one proprietary platform.
• Studies differ in patient phenotype, wavelength combinations, irradiance, exposure time, frequency, endpoints and follow-up.
• Independent PBM4AMD findings suggest that some functional gains may diminish over time.
• Current meta-analyses are considered insufficient to establish definitive efficacy.
• Optimal wavelength, irradiance, fluence, treatment duration and treatment frequency remain unresolved.
• One author, Serge Mordon, is a co-founder of Hemerion Therapeutics, although the authors state that the company did not participate in the review or publication decision.

Bottom line

The paper provides a useful explanation for why the same PBM protocol might help some AMD patients but not others:

Response = appropriate light dose × sufficient remaining mitochondrial reserve.

It supports PBM as a biologically plausible and promising metabolic intervention, especially in early and intermediate AMD, but concludes that PBM remains exploratory. The evidence is not yet sufficient to establish definitive clinical efficacy, confirmed disease modification, a validated responder profile or an optimal dosing protocol.

For a monowavelength 670 nm device, the paper strengthens the mitochondrial rationale but does not independently validate a particular 670 nm irradiance, fluence, frequency or home-treatment schedule. Most of the reviewed controlled AMD evidence involves multiwavelength treatment rather than 670 nm alone.