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A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.

Maddison, Daniel C. ORCID: https://orcid.org/0000-0003-3038-1687, Alfonso-Núñez, Mónica, Swaih, Aisha M., Breda, Carlo, Campesan, Susanna, Allcock, Natalie, Straatman-Iwanowska, Anna, Kyriacou, Charalambos P. and Giorgini, Flaviano 2020. A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics. PLoS Genetics 16 (11) , e1009129. 10.1371/journal.pgen.1009129

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Abstract

The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article distributed under the terms of the Creative Commons Attribution License
Publisher: Public Library of Science
ISSN: 1553-7404
Date of First Compliant Deposit: 4 August 2022
Date of Acceptance: 22 September 2020
Last Modified: 06 Jan 2024 04:40
URI: https://orca.cardiff.ac.uk/id/eprint/151325

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