A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics, 2020, Giorgini et al

Andy · Nov 11, 2020

In flys.

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.

Author summary
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.
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Open access, https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009129

Creekside · Nov 11, 2020

I'm convinced that problems in the cerebral kynurenine system are a significant part of my ME, so this paper provides another possible explanation for how.

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A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics, 2020, Giorgini et al

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A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics, 2020, Giorgini et al

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