Metabolic pathways consist of a series of biochemical reactions in cells that convert a starting component into other products. There is growing evidence that metabolic pathways are coupled with external stress factors influencing the health of cells and tissues. Many human diseases, including retinal or neurodegenerative diseases, are associated with imbalances in metabolic pathways.
The kynurenine pathway is an evolutionary conserved metabolic pathway that regulates a variety of biological processes. Its disruption can result in the buildup of either toxic or protective biomolecules or metabolites, which can worsen or improve, respectively, the health of the brain, including the retina. Knowledge on this important metabolic pathway was recently extended by the research team, led by Elisabeth Knust, Director Emerita at the MPI-CBG, in their publication in the journal Plos Genetics. Being aware of 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 looked at four genes — cinnabar, cardinal, white, and scarlet – named after abnormal eye colors following their loss in flies. “Since the kynurenine pathway is conserved from flies to humans, we asked whether these genes regulate retinal health independent of their role in pigment formation,” says Sarita Hebbar, one of the lead authors of the study.
To find this out, the scientists used a combination of genetics, dietary changes, and biochemical analysis of metabolites to study different mutations of the fruit fly. Drosophila melanogaster. Sofia Traikov, a co-author, developed a method for the biochemical analysis of the metabolites of the Kynurenine pathway. This allowed the researchers to link different metabolite levels to the health state of the retina. They found that one metabolite, 3-hydroxykynurenine (3OH-K), is damaging to 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 by their absolute amounts. Sarita continues: “We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K enhanced stress-induced retinal damage, whereas KYNA protected the retina from stress-related damage.” This means that retinal health in certain conditions can be improved by altering the ratio of metabolites of the Kynurenine pathway.
Furthermore, by targeting these four genes and therefore four distinct steps within the pathway, the researchers were able to demonstrate that not only the accumulation of 3OH-K as such, but also its location in the cell and hence its availability in further reactions, is important for regular health.
“This work shows that the Kynurenine pathway is important not only in pigment formation but that the level of individual metabolites fulfills important roles in maintaining retinal health,” says Elisabeth Knust, who supervised the study. She concludes, “In the future, the ratio of the various metabolites and the specific sites of their accumulation and activity should be taken into account in therapeutic strategies for diseases with impaired kynurenine pathway function, observed in various neurodegenerative conditions.”
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