{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T16:18:26Z","timestamp":1792858706315,"version":"4.5.0"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004189","name":"Max-Planck-Gesellschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>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<jats:italic>Drosophila melanogaster<\/jats:italic>.<jats:italic>cinnabar<\/jats:italic>,<jats:italic>cardinal<\/jats:italic>and<jats:italic>scarlet<\/jats:italic>are fly genes that encode different steps in the KP. Along with<jats:italic>white<\/jats:italic>, these genes are known regulators of brown pigment (ommochrome) biosynthesis. Using<jats:italic>white<\/jats:italic>as a sensitized genetic background, we show that mutations in<jats:italic>cinnabar<\/jats:italic>,<jats:italic>cardinal<\/jats:italic>and<jats:italic>scarlet<\/jats:italic>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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010644","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T18:26:01Z","timestamp":1679595961000},"page":"e1010644","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-9413","authenticated-orcid":true,"given":"Sarita","family":"Hebbar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-8454","authenticated-orcid":true,"given":"Sofia","family":"Traikov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrin","family":"H\u00e4lsig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-9135","authenticated-orcid":true,"given":"Elisabeth","family":"Knust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"issue":"11","key":"pgen.1010644.ref001","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.15252\/embj.201695810","article-title":"Brain metabolism in health, aging, and neurodegeneration","volume":"36","author":"S Camandola","year":"2017","journal-title":"EMBO J"},{"key":"pgen.1010644.ref002","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.3389\/fphys.2019.01254","article-title":"Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes","volume":"10","author":"M Fiedorowicz","year":"2019","journal-title":"Front Physiol."},{"issue":"10","key":"pgen.1010644.ref003","article-title":"Metabolomics in Retinal Diseases: An Update","volume":"10","author":"X Li","year":"2021","journal-title":"Biology (Basel)"},{"issue":"1","key":"pgen.1010644.ref004","first-page":"245","article-title":"Photoreceptor metabolic reprogramming: current understanding and therapeutic implications","volume":"4","author":"WW Pan","year":"2021","journal-title":"Commun Biol.PubMed Central PMCID"},{"issue":"1","key":"pgen.1010644.ref005","doi-asserted-by":"crossref","first-page":"17863","DOI":"10.1038\/s41598-017-18098-z","article-title":"Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration","volume":"7","author":"TJ Wubben","year":"2017","journal-title":"Sci Rep."},{"issue":"7","key":"pgen.1010644.ref006","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1586\/14737175.2015.1049999","article-title":"What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?","volume":"15","author":"I Davis","year":"2015","journal-title":"Expert Rev Neurother."},{"issue":"2","key":"pgen.1010644.ref007","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0021-9258(18)65682-0","article-title":"Kynurenine formamidase from Neurospora","volume":"207","author":"WB Jakoby","year":"1954","journal-title":"J Biol Chem"},{"issue":"4","key":"pgen.1010644.ref008","first-page":"763","article-title":"Xanthurenic acid in the mutant strain scarlet of DROSOPHILA MELANOGASTER","volume":"82B","author":"Y Umebachi","year":"1985","journal-title":"Comp Biochem PhysioL"},{"key":"pgen.1010644.ref009","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.neuro.2012.11.007","article-title":"3-Hydroxykynurenine: an intriguing molecule exerting dual actions in the central nervous system","volume":"34","author":"AL Colin-Gonzalez","year":"2013","journal-title":"Neurotoxicology"},{"key":"pgen.1010644.ref010","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/7854_2016_6","article-title":"Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression","volume":"31","author":"R. 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