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://doi.org/10.1371/journal.pgen.1010644 |
| _version_ | 1797850309910855680 |
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| author | Sarita Hebbar Sofia Traikov Catrin Hälsig Elisabeth Knust |
| author_facet | Sarita Hebbar Sofia Traikov Catrin Hälsig Elisabeth Knust |
| author_sort | Sarita Hebbar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T18:59:22Z |
| format | Article |
| id | doaj.art-8779d396c6f64584b00e97d432ec342f |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-09T18:59:22Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-8779d396c6f64584b00e97d432ec342f2023-04-09T05:31:55ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-03-01193e101064410.1371/journal.pgen.1010644Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila.Sarita HebbarSofia TraikovCatrin HälsigElisabeth KnustTissue 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.https://doi.org/10.1371/journal.pgen.1010644 |
| spellingShingle | Sarita Hebbar Sofia Traikov Catrin Hälsig Elisabeth Knust Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. PLoS Genetics |
| title | Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. |
| title_full | Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. |
| title_fullStr | Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. |
| title_full_unstemmed | Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. |
| title_short | Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. |
| title_sort | modulating the kynurenine pathway or sequestering toxic 3 hydroxykynurenine protects the retina from light induced damage in drosophila |
| url | https://doi.org/10.1371/journal.pgen.1010644 |
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