Metabolic pathways consist of a series of biochemical reactions in cells that convert a starting component into other products. There is increasing evidence that metabolic pathways associated with extrinsic stressors affect cell and tissue health. Many human diseases, including retinal or neurodegenerative diseases, are associated with imbalances in metabolic pathways.
Elisabeth Knust leads a team of researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, who describe the essential role of one such metabolic pathway in maintaining retinal health under conditions of stress. They studied the classic Drosophila genes vermilion, cardinal, white, and scarlet, originally characterized decades ago and named for their role in eye color pigmentation, particularly in the formation of the brown eye pigment of flies.
These genes encode components of the kynurenine pathway, the activity of which converts the amino acid tryptophan into other products in various steps. In this study, the authors highlighted the function of this metabolic pathway in retinal health, independent of its role in pigment formation.
The kynurenine pathway is an evolutionarily conserved metabolic pathway that regulates a number of biological processes. Its disruption can result in the accumulation of either toxic or protective biomolecules or metabolites, which can worsen or improve the health of the brain, including the retina. Knowledge of this important metabolic pathway was recently expanded by a research team led by Elisabeth Knust, MPI-CBG director emeritus, in their publication in the journal Plos Genetics.
Recognizing the remarkable conservation of this metabolic pathway and the genes that regulate it, they used flies as a model system to unravel the role of individual metabolites in retinal health. The researchers examined four genes vermilion, cardinal, white and scarlet named after the abnormal eye colors after their loss in flies.
“Since the kynurenine pathway is conserved from flies to humans, we asked whether these genes regulate retinal health independently of their role in pigment formation,” says Sarita Hebbar, one of the lead authors of the study.
To find out, the researchers used a combination of genetics, dietary changes and biochemical analysis of metabolites to study different mutations of the fruit fly Drosophila melanogaster. Sofia Traikov, co-author, developed a method for biochemical analysis of kynurenine pathway metabolites. This allowed researchers to link different levels of metabolites to retinal health.
They found that one metabolite, 3-hydroxykynurenine (3OH-K), damages the retina. More importantly, they could show that the degree of degeneration is influenced by the balance between toxic 3OH-K and protective metabolites such as kynurenic acid (KYNA), and not just their absolute amount. Sarita continues, “We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K increased stress-induced retinal damage, while KYNA protected the retina from stress-related damage.”
This means that retinal health under certain conditions can be improved by changing the ratio of kynurenine pathway metabolites.
Furthermore, by targeting these four genes, and thus four distinct steps in the pathway, the researchers were able to demonstrate that not only the accumulation of 3OH-K per se, but also its location in the cell, and thus its availability in further reactions, is important for health retina.
“This work shows that the kynurenine pathway is not only important in pigment formation, but that individual metabolite levels play an important role in maintaining retinal health,” says Elisabeth Knust, who supervised the study.
He concludes: “In the future, the ratio of different metabolites and the specific sites of their accumulation and activity should be taken into account in therapeutic strategies for diseases with impaired function of the kynurenine pathway, observed in various neurodegenerative conditions.”
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