Neurotoxicity Research

, Volume 35, Issue 3, pp 530–541 | Cite as

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. LovejoyEmail author
  • Gilles J. GuilleminEmail author
Original Article


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.


Kynurenine pathway Kynurenine 3-monooxygenase Oxidative stress Mitochondrial dysfunction 





Anthranilic acid


Alzheimer’s disease


Central nervous system






Electron transport system


Flavin adenine dinucleotide


Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone


Hydrogen peroxide


Huntington’s Disease


High-performance liquid chromatography


Indoleamine 2,3-dioxygenase 1


Indoleamine 2,3-dioxygenase 2


Interferon gamma


Kynurenine aminotransferase


Kynurenine 3-monooxygenase


Kynurenine pathway




Kynurenic acid




Maximal respiration


Nicotinamide adenine dinucleotide


Nicotinamide adenine dinucleotide phosphate




Oxygen consumption rate


Phosphate-buffered saline


Quinolinic acid


Rhodamine 123


Reactive oxygen species


Residual oxygen consumption/non-mitochondrial respiration


Room temperature


Spare respiratory capacity


Tryptophan 2,3-dioxygenase




Ultra-high performance liquid chromatography


α-7 nicotinic acetyl choline receptor


Mitochondrial membrane potential



This work was supported by the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC), Macquarie University, The Snow Foundation and the Ramaciotti Perpetual Foundation (Australia). Dr. Gloria Castellano-Gonzalez was a recipient of the Macquarie University international scholarship.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Gloria Castellano-Gonzalez
    • 1
  • Kelly R. Jacobs
    • 1
  • Emily Don
    • 2
  • Nicholas J. Cole
    • 2
  • Seray Adams
    • 1
  • Chai K. Lim
    • 1
  • David B. Lovejoy
    • 1
    Email author
  • Gilles J. Guillemin
    • 1
    Email author
  1. 1.Neuroinflammation Group, Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences (FMHS)Macquarie UniversityNorth RydeAustralia
  2. 2.Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences (FMHS)Macquarie UniversityNorth RydeAustralia

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