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Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022 by the authors.The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD)—which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO. In order to test this hypothesis, we employed bimolecular fluorescence complementation (BiFC) and found that KMO physically interacts with soluble HTT exon 1 protein fragment in living cells. Notably, expansion of the disease-causing polyglutamine tract in HTT leads to the formation of proteinaceous intracellular inclusions that disrupt this interaction with KMO, markedly decreasing BiFC efficiency. Using confocal microscopy and ultrastructural analysis, we determined KMO and HTT localisation within the cell and found that the KMO-HTT interaction is localized to the outer mitochondrial membrane. These data suggest that KMO may interact with a pool of HTT at the mitochondrial membrane, highlighting a possible physiological role for mitochondrial HTT. The KMO-HTT interaction is abrogated upon polyglutamine expansion, which may indicate a heretofore unrecognized relevance in the pathogenesis of this disorder.

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Author(s): Swaih AM, Breda C, Sathyasaikumar KV, Allcock N, Collier MEW, Mason RP, Feasby A, Herrera F, Outeiro TF, Schwarcz R, Repici M, Giorgini F

Publication type: Article

Publication status: Published

Journal: Biomedicines

Year: 2022

Volume: 10

Issue: 9

Online publication date: 15/09/2022

Acceptance date: 09/09/2022

Date deposited: 11/10/2022

ISSN (electronic): 2227-9059

Publisher: MDPI

URL: https://doi.org/10.3390/biomedicines10092294

DOI: 10.3390/biomedicines10092294

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