Kynurenine 3-monooxygenase activity in human primary neurons and effect on cellular bioenergetics identifies new neurotoxic mechanisms

Gloria Castellano-Gonzalez, Kelly R. Jacobs, Emily Don, Nicholas J. Cole, Seray Adams, Chai K. Lim, David B. Lovejoy*, Gilles J. Guillemin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has been described in neurodegenerative disease including Alzheimer’s disease and Huntington’s disease. In this study, we characterise KMO activity in human primary neurons and identified new mechanisms by which KMO activation mediates neurotoxicity. We show that while transient activation of the KP promotes synthesis of the essential co-enzyme nicotinamide adenine dinucleotide (NAD+), allowing cells to meet short-term increased energy demands, chronic KMO activation induces production of reactive oxygen species (ROS), mitochondrial damage and decreases spare-respiratory capacity (SRC). We further found that these events generate a vicious-cycle, as mitochondrial dysfunction further shunts the KP towards the KMO branch of the KP to presumably enhance QUIN production. These mechanisms may be especially relevant in neurodegenerative disease as neurons are highly sensitive to oxidative stress and mitochondrial impairment.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalNeurotoxicity Research
Volume35
Issue number3
Early online date21 Jan 2019
DOIs
Publication statusPublished - Apr 2019

Keywords

  • Kynurenine 3-monooxygenase
  • Kynurenine pathway
  • Mitochondrial dysfunction
  • Oxidative stress

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