Document type
Journal articles
Document subtype
Full paper
Title
Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane
Participants in the publication
Aisha M. Swaih (Author)
Carlo Breda (Author)
Korrapati V. Sathyasaikumar (Author)
Natalie Allcock (Author)
Mary E. W. Collier (Author)
Robert P. Mason (Author)
Adam Feasby (Author)
Federico Herrera (Author)
Dep. Química e Bioquímica
BioISI
Tiago F. Outeiro (Author)
Robert Schwarcz (Author)
Mariaelena Repici (Author)
Flaviano Giorgini (Author)
Summary
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.
Date of Publication
2022-09-15
Institution
BioISI - Biosystems & Integrative Sciences Institute
Where published
Biomedicines
Publication Identifiers
ISSN - 2227-9059
Publisher
MDPI AG
Document Identifiers
DOI -
https://doi.org/10.3390/biomedicines10092294
URL -
http://dx.doi.org/10.3390/biomedicines10092294
Rankings
SCIMAGO Q1 (2021) - 874 - Medicine (miscellaneous)
Web Of Science Q2 (2021) - 4.757 - MEDICINE, RESEARCH & EXPERIMENTAL - SCIE
SCOPUS Q2 (2021) - 3 - General Biochemistry, Genetics and Molecular Biology
Keywords
neurodegeneration
huntington disease
huntingtin
kinureamines
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