Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.
Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.
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DOI：
10.3390/biomedicines10092294
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发表时间：
2022-09-15
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
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黄素蛋白犬尿氨酸3-单加氧酶（KMO）定位于线粒体外膜，并催化从L-犬尿氨酸合成3-羟基犬尿氨酸，这是色氨酸降解的犬尿氨酸途径（KP）中的关键步骤。由于炎症引起的KP代谢的扰动长期以来与几种神经退行性疾病的发病机制相关，包括亨廷顿病（HD）-其由亨廷顿（HTT）蛋白中的多聚谷氨酰胺延伸的扩展引起。虽然HTT主要定位于细胞质，但它也与线粒体相关，在那里它可能与KMO发生物理相互作用。为了验证这一假设，我们采用双分子荧光互补（BiFC），发现KMO与活细胞中可溶性HTT外显子1蛋白片段发生物理相互作用。值得注意的是，HTT中致病的多聚谷氨酰胺束的扩张导致蛋白质细胞内包涵体的形成，破坏了与KMO的相互作用，显著降低了BiFC的效率。使用共聚焦显微镜和超微结构分析，我们确定KMO和HTT定位在细胞内，发现KMO-HTT相互作用定位于外线粒体膜。这些数据表明，KMO可能与线粒体膜上的HTT池相互作用，突出了线粒体HTT可能的生理作用。KMO-HTT相互作用在多聚谷氨酰胺扩增后被废除，这可能表明在这种疾病的发病机制中迄今未被认识到的相关性。
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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DOI：
10.1371/currents.rrn1210
发表时间：
2011-02-11
期刊：
PLoS currents
影响因子：
--
作者：
Herrera F;Tenreiro S;Miller-Fleming L;Outeiro TF
通讯作者：
Outeiro TF
DOI：
10.1177/1073858410390378
发表时间：
2011-10
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Ehrnhoefer DE;Sutton L;Hayden MR
通讯作者：
Hayden MR
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1007/978-3-319-71779-1_3
发表时间：
2018-01-01
期刊：
POLYGLUTAMINE DISORDERS
影响因子：
--
作者：
Carmo, Catarina;Naia, Luana;Cristina Rego, A.
通讯作者：
Cristina Rego, A.
影响因子：
4.5
作者：
Maddison DC;Alfonso-Núñez M;Swaih AM;Breda C;Campesan S;Allcock N;Straatman-Iwanowska A;Kyriacou CP;Giorgini F
通讯作者：
Giorgini F