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.

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）的关键分支点工作。由于KP与几种人类疾病的发病机制有关，因此KMO和其他控制代谢途径代谢的酶是这些疾病的潜在治疗靶标。尽管在真核生物中KMO定位于线粒体外膜，但尚未描述KMO的线粒体作用。在这项研究中，KMO缺陷型果蝇进行了调查线粒体表型在体外和体内。我们发现果蝇KMO直系同源基因（朱砂）的功能等位基因或RNAi敲低缺失）引起线粒体的一系列形态学和功能性变化，而这些变化与KP代谢物水平的变化无关。值得注意的是，朱砂基因与帕金森氏症相关的基因相互作用PINK1和帕金，以及线粒体裂变基因DRP1，线粒体动力学和自噬，支配健康的线粒体网络的维护机制牵连KMO。发现人类KMO在哺乳动物细胞中的过度表达发现KMO在DRP1的翻译后调控中起作用。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。