(Ebeling et al., 2020 | Redox Biology) An illustration of the functions of the four molecules tested in age-related macular degeneration eye cells. NAC protects mitochondria, increasing numbers of healthy mitochondria. Rapamycin stimulates the clearance of defective mitochondria through a process called mitophagy. PQQ stimulates the production of mitochondria through a process called biogenesis. NMN increases the amount of cellular energy molecules, adenosine triphosphate (ATP), through a process called oxidative phosphorylation.

Age-related macular degeneration (AMD) constitutes the leading cause of vision loss in adults and affects 20-30% of people over 75 years of age in developed nations. AMD is caused by the  deterioration of a small area toward the center of the eye, the macula, resulting in vision loss in the center of the field of vision. 

Individuals with AMD have difficulties reading, recognizing faces, and visualizing fine detail. Current treatments for AMD can only treat about 10% of the patients, those with “wet” AMD, where blood vessels grow into the center of the eye. No treatment options currently exist for the other 90% of patients with “dry” AMD who lose cells in their retina, the light-sensitive tissue of the eye.

As past studies indicate that defects in the mitochondria, the cell’s energy generator, are key aspects of the AMD disease, scientists targeted the organelle to confront dry AMD therapeutically. The research team from the University of Minnesota Department of Ophthalmology published a study in Redox Biology, May 2020 where they treated mitochondrial dysfunction in cells from AMD patients with four molecules, N-acetyl-L-cysteine (NAC), Rapamycin, Pyrroloquinoline quinone (PQQ), and nicotinamide mononucleotide (NMN). Cells from different AMD patients exhibited a distinct reaction to each drug suggesting the potential of developing personalized treatments for individuals with AMD. In other words, some treatments work in certain patients and not others so that clinicians could evaluate which treatments are most effective in each individual.

The group of researchers chose the four molecules based on their effects on mitochondria. NAC increases energy molecules in cells, adenosine triphosphate (ATP) molecules, by protecting mitochondria from oxidative stress and increasing numbers of mitochondria which produce ATP.  Researchers also identified PQQ as a potent molecule because of its ability to increase mitochondrial content in cells through stimulating mitochondria production. Besides increasing the number of mitochondria, inducing the disposal of defective mitochondria from the cell in a process called mitophagy with rapamycin also improves mitochondrial function. NMN boosts the concentration of a molecule called nicotinamide adenine dinucleotide (NAD+), which contributes to the production of cellular energy and promotion of cellular health.

Mitochondria produce ATP through a process called oxidative phosphorylation for energy throughout the body, and by measuring the ATP levels, scientists can evaluate how well the mitochondria function. Treatment of cells with the four molecules only improved mitochondrial function in some of the AMD patients.  Rapamycin, PGG and NMN significantly increased ATP levels in patients’ retinal cells but NAC did not.

(Ebeling et al., 2020 | Redox Biology) The four molecules increase energy production in some of the donors’ eye cells, the retinal pigment epithelium. The box on the left shows data for cells from donors without age-related macular degeneration, and the box on the right shows data for cells from donors with age-related macular degeneration. The “fold change” refers to levels in comparison to levels of the energy molecule, ATP, without treatment, which equals one. Some of the patients, but not all, responded to treatment from the four molecules. The raised ATP levels were statistically significant in Rapamycin, PQQ, and NMN.

The retinal cells from half of the patients showed a 50% to 350% improvement in mitochondrial function with treatment, while the other half showed 5% to 25% improvement in mitochondrial function. Cells from different patients exhibit highly individualized responses to the molecules.

 “These results support the idea that an individualized approach to treating AMD is required,” stated the scientists in their study. “Developing ways to pre-screen patients to determine the optimal type of intervention is a critical linchpin in finding effective treatments for AMD.” 

The scientists also compared the results from treatments with each of the four molecules and found PQQ as the most effective in improving mitochondrial function since PQQ treatment gave the most robust improvements in mitochondrial function. Although variability existed in the treatment responses, a particular molecule or combination of molecules could lead to better treatment responses.