A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.
A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.
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DOI：
10.1371/journal.pgen.1009129
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发表时间：
2020-11
期刊：
影响因子：
4.5
通讯作者：
Giorgini F
中科院分区：
文献类型：
--
作者：
Maddison DC;Alfonso-Núñez M;Swaih AM;Breda C;Campesan S;Allcock N;Straatman-Iwanowska A;Kyriacou CP;Giorgini F
犬尿氨酸3-单加氧酶（KMO）在犬尿氨酸途径（KP）（色氨酸代谢的主要途径）中的关键分支点处起作用。由于KP与几种人类疾病的发病机制有关，因此KMO和控制通过该途径的代谢通量的其他酶是这些疾病的潜在治疗靶点。虽然KMO定位于真核生物中的线粒体外膜，但尚未描述KMO的线粒体作用。在这项研究中，KMO缺陷的果蝇线粒体表型进行了调查，在体外和体内。我们发现，果蝇KMO直系同源物（朱砂）的功能等位基因或RNAi敲低的损失导致线粒体的一系列形态和功能改变，这是独立的KP代谢物水平的变化。值得注意的是，朱砂在遗传上与帕金森病相关基因Pink 1和parkin以及线粒体裂变基因Drp 1相互作用，暗示KMO参与线粒体动力学和线粒体自噬，这是管理健康线粒体网络维持的机制。人KMO在哺乳动物细胞中的过表达发现，KMO在DRP 1的翻译后调节中起作用。这些发现揭示了KMO的一种新的线粒体作用，独立于其在犬尿氨酸途径中的酶促作用。线粒体受到质量控制机制的影响以维持稳态，定期进行分裂和融合以拯救受损的细胞器或分离受损无法修复的区域，然后通过线粒体自噬清除。这些质量控制机制与许多神经退行性疾病有关，包括家族性帕金森病，这可能是由两个线粒体自噬控制基因PINK 1和PRKN突变引起的。犬尿氨酸途径是膳食色氨酸代谢的途径。该通路有多个分支点，通过这些分支的流量不平衡与神经退行性疾病有关。犬尿氨酸3-单加氧酶（KMO）位于控制途径平衡的关键分支点。KMO定位于线粒体，但迄今为止，任何特定的功能是未知的。在这项研究中，我们证明，KMO通过分裂因子DRP 1在线粒体分裂中发挥作用，KMO缺乏导致线粒体形态和功能的变化。在果蝇中操纵KMO也证明了与PINK 1和PRKN的相互作用。有趣的是，这些相互作用似乎独立于KMO在犬尿氨酸途径中的已知酶作用，证明了该蛋白质的新的独立功能。
The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway. Mitochondria are subject to quality control mechanisms to maintain homeostasis, regularly undergoing fission and fusion to rescue damaged organelles or segregate regions that are damaged beyond repair which are then cleared by mitophagy. These quality control mechanisms have been implicated in a number of neurodegenerative diseases, including familial Parkinson’s disease, which can be caused by mutations in two mitophagy governing genes, PINK1 and PRKN. The kynurenine pathway is a pathway through which dietary tryptophan is metabolised. The pathway has multiple branchpoints and an imbalance in flux through these branches has been associated with neurodegenerative disease. The enzyme kynurenine 3-monooxygenase (KMO) sits at a critical branchpoint controlling balance in the pathway. KMO is localised to mitochondria, yet to date any mitochondria-specific function is unknown. In this study, we demonstrate that KMO plays a role in mitochondrial fission via the fission factor DRP1 and that KMO deficiency leads to changes in mitochondrial morphology and function. Manipulation of KMO in Drosophila melanogaster also demonstrates an interaction with PINK1 and PRKN. Intriguingly, these interactions appear to be independent of the known enzymatic role of KMO in the kynurenine pathway, demonstrating a novel and independent function of the protein.