Tipo
Artigos em Revista
Tipo de Documento
Artigo Completo
Título
Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane
Participantes na publicação
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)
Resumo
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.
Data de Publicação
2022-09-15
Instituição
BioISI - Biosystems & Integrative Sciences Institute
Suporte
Biomedicines
Identificadores da Publicação
ISSN - 2227-9059
Editora
MDPI AG
Identificadores do Documento
DOI -
https://doi.org/10.3390/biomedicines10092294
URL -
http://dx.doi.org/10.3390/biomedicines10092294
Identificadores de Qualidade
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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