A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

PLoS Genet. 2020 Nov 10;16(11):e1009129. doi: 10.1371/journal.pgen.1009129. eCollection 2020 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Dynamins / metabolism
  • Epistasis, Genetic
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Kynurenine / metabolism*
  • Kynurenine 3-Monooxygenase / genetics
  • Kynurenine 3-Monooxygenase / metabolism*
  • Male
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics / genetics*
  • Mitophagy / genetics
  • Mutation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Up-Regulation

Substances

  • Drosophila Proteins
  • Kynurenine
  • Kynurenine 3-Monooxygenase
  • Ubiquitin-Protein Ligases
  • PINK1 protein, Drosophila
  • Protein Serine-Threonine Kinases
  • DNM1L protein, human
  • Dynamins
  • park protein, Drosophila