Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila
Tissue health is regulated by a myriad of exogenous or endogenous factors. Here we investigated the role of the conserved Kynurenine pathway (KP) in maintaining retinal homeostasis in the context of light stress in Drosophila melanogaster. cinnabar, cardinal and scarlet are fly genes that encode dif...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035932/?tool=EBI |
| Summary: | Tissue health is regulated by a myriad of exogenous or endogenous factors. Here we investigated the role of the conserved Kynurenine pathway (KP) in maintaining retinal homeostasis in the context of light stress in Drosophila melanogaster. cinnabar, cardinal and scarlet are fly genes that encode different steps in the KP. Along with white, these genes are known regulators of brown pigment (ommochrome) biosynthesis. Using white as a sensitized genetic background, we show that mutations in cinnabar, cardinal and scarlet differentially modulate light-induced retinal damage. Mass Spectrometric measurements of KP metabolites in flies with different genetic combinations support the notion that increased levels of 3-hydroxykynurenine (3OH-K) and Xanthurenic acid (XA) enhance retinal damage, whereas Kynurenic Acid (KYNA) and Kynurenine (K) are neuro-protective. This conclusion was corroborated by showing that feeding 3OH-K results in enhanced retinal damage, whereas feeding KYNA protects the retina in sensitized genetic backgrounds. Interestingly, the harmful effects of free 3OH-K are diminished by its sub-cellular compartmentalization. Sequestering of 3OH-K enables the quenching of its toxicity through conversion to brown pigment or conjugation to proteins. This work enabled us to decouple the role of these KP genes in ommochrome formation from their role in retinal homeostasis. Additionally, it puts forward new hypotheses on the importance of the balance of KP metabolites and their compartmentalization in disease alleviation. Author summary Intracellular metabolic pathways regulate tissue homeostasis. Less understood are (i) the role of specific metabolic intermediates, and (ii) the interplay between metabolic perturbation and heightened stress. These were addressed in the D.melanogaster (fly) retina using a light stress paradigm in the context of the conserved Kynurenine pathway (KP). Genes that encode distinct steps of the KP (cinnabar, cardinal and scarlet), along with white, are also the genetic regulators of brown pigment biosynthesis in the fly retina. With white as a sensitized genetic background, mutations in KP genes differentially modulated light-induced retinal damage. Connecting Mass Spectrometric measurements of KP metabolic intermediates with retinal health showed that increased levels of 3-hydroxykynurenine (3OH-K) and Xanthurenic acid enhanced tissue damage, whereas Kynurenic Acid (KYNA) and Kynurenine are protective. Feeding metabolic intermediates (3OH-K or KYNA) corroborated the above. This has helped to decouple the role of KP genes in pigment formation from their role in retinal homeostasis. Studying these KP genes enabled to better understand the importance of compartmentalization in metabolism. Sequestering of 3OH-K enables the quenching of its toxicity through conversion to brown pigment or conjugation to proteins. In a broad context, it highlights the relevance of compartmentalization of KP metabolites in disease alleviation. |
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| ISSN: | 1553-7390 1553-7404 |