Eye color genes play a role in determining the color of an individual’s eyes, but they are not directly related to retinal health. The retina is part of the eye that is responsible for receiving and processing visual information. While eye color is determined by the amount and type of pigment in the iris, retinal health is influenced by a variety of factors, including genetics, nutrition, and lifestyle.
Metabolic pathways are a series of biochemical reactions in cells that convert a starting component into other products. There is mounting evidence that metabolic pathways, in conjunction with external stressors, influence the health of cells and tissues. Many human diseases, such as retinal or neurodegenerative diseases, are linked to metabolic pathway imbalances.
Elisabeth Knust leads a team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, who describe one such metabolic pathway’s critical role in maintaining retinal health under stress. They investigated the classic Drosophila genes cinnabar, cardinal, white, and scarlet, which were discovered and named decades ago due to their role in eye color pigmentation, specifically the formation of the brown pigment of the fly eye. These genes encode components of the kynurenine pathway, which converts the amino acid tryptophan into other products through a series of steps. The authors of this study highlighted the role of this metabolic pathway in retinal health, independent of its role in pigment formation.
This work demonstrates that the Kynurenine pathway is important not only in pigment formation, but that the levels of individual metabolites play important roles in maintaining retinal health.
Elisabeth Knust
The Kynurenine pathway is a metabolic pathway that has been conserved throughout evolution and regulates a variety of biological processes. Its disruption can lead to the accumulation of either toxic or protective biomolecules or metabolites, which can either worsen or improve the health of the brain, including the retina. The research team led by Elisabeth Knust, Director Emerita at the MPI-CBG, recently extended knowledge on this important metabolic pathway in their publication in the journal Plos Genetics.
They used flies as a model system to investigate the role of individual metabolites in retinal health because of the remarkable conservation of this metabolic pathway and the genes that regulate it. The researchers examined four genes named after abnormal eye colors after their loss in flies: cinnabar, cardinal, white, and scarlet. “Because the Kynurenine pathway is conserved from flies to humans, we wondered if these genes regulate retinal health apart from their role in pigment formation,” says Sarita Hebbar, one of the study’s lead authors.
The scientists studied different mutations of the fruit fly, Drosophila melanogaster, using a combination of genetics, dietary changes, and biochemical analysis of metabolites. Sofia Traikov, a co-author, created a method for analyzing the metabolites of the Kynurenine pathway biochemically. This enabled the researchers to establish a link between different metabolite levels and retinal health. They discovered that one of the metabolites, 3-hydroxykynurenine (3OH-K), is harmful to the retina. More importantly, they may demonstrate that the degree of degeneration is influenced by the balance of toxic 3OH-K and protective metabolites, such as Kynurenic Acid (KYNA), rather than their absolute amounts.
“We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K increased stress-induced retinal damage, whereas KYNA protected the retina from stress-related damage,” Sarita continues. This means that changing the ratio of metabolites in the Kynurenine pathway can improve retinal health in certain conditions.
Furthermore, by targeting these four genes and thus four distinct steps within the pathway, the researchers were able to demonstrate that not only 3OH-K accumulation, but also its location in the cell and thus its availability in subsequent reactions, is important for retinal health.
“This work demonstrates that the Kynurenine pathway is important not only in pigment formation, but that the levels of individual metabolites play important roles in maintaining retinal health,” says study supervisor Elisabeth Knust. “In the future, the ratio of the various metabolites, as well as the specific sites of their accumulation and activity, should be taken into account in therapeutic strategies for diseases with impaired Kynurenine pathway function, as observed in various neurodegenerative conditions,” she concludes.
