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

Abstract

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.

Publication DOI: https://doi.org/10.3390/biomedicines10092294
Divisions: College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Additional Information: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/) Funding Information: A.M.S. was funded by the Libyan Ministry of Education as part of a doctoral degree. C.B., M.R., R.P.M. and F.G. were supported by M.R.C. project grants (MR/N00373X/1, MR/L003503/1, MR/R011621/1). M.E.W.C. and F.G. have funding from the National Institute of Mental Health (Silvio O. Conte Center for Translational Mental Health Research—MH-103222). T.F.O. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2067/1—390729940. F.H. was supported by centre grants UIDB/04046/2020 and UID/MULTI/04046/2020 (to BioISI) and national funds through Fundação para a Ciência e Tecnologia (Ref. PTDC/MED-NEU/31417/2017). K.V.S. and R.S. received support from USPHS grant MH103222. Open access publication charges were paid by the University of Leicester Library.
Uncontrolled Keywords: Article,kynurenine 3-monooxygenase,Huntington’s disease,huntingtin,mitochondria,BiFC,live cell imaging
Publication ISSN: 2227-9059
Last Modified: 27 May 2024 07:39
Date Deposited: 07 Oct 2022 08:10
Full Text Link:
Related URLs: https://www.mdp ... -9059/10/9/2294 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2022-09-15
Published Online Date: 2022-09-15
Accepted Date: 2022-09-09
Submitted Date: 2022-08-29
Authors: Swaih, Aisha M.
Breda, Carlo
Sathyasaikumar, Korrapati V.
Allcock, Natalie
Collier, Mary E. W.
Mason, Robert P.
Feasby, Adam
Herrera, Federico
Outeiro, Tiago F.
Schwarcz, Robert
Repici, Mariaelena (ORCID Profile 0000-0002-9420-528X)
Giorgini, Flaviano

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