Abstract
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.
Highlights
The kynurenine pathway (KP) (Fig 1) is the major route of tryptophan metabolism in eukaryotes and has been implicated in the pathology of several human diseases, brain disorders including neurodegeneration, schizophrenia and depression [1,2]
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 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, PTEN-induced kinase 1 (PINK1) and PRKN
Summary
The kynurenine pathway (KP) (Fig 1) is the major route of tryptophan metabolism in eukaryotes and has been implicated in the pathology of several human diseases, brain disorders including neurodegeneration, schizophrenia and depression [1,2]. The connection between the KP and pathology varies between disorders, one common feature is the imbalance in metabolites produced through distinct branches of the KP. For this reason, enzymes that control the rate of flux through the pathway have become candidate drug targets for the treatment of these diseases. Enzymes that control the rate of flux through the pathway have become candidate drug targets for the treatment of these diseases Both genetic and pharmacological manipulation of KP enzymes is protective in yeast, Drosophila melanogaster and mammalian models of neurodegeneration [3,4,5,6]. Several drugs inhibiting KMO have been developed which hold promise as potential therapeutic agents for neurodegenerative disease [3,6,7]
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