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Castellano-Gonzalez 2019 Neurotox Res
Additional label 2019-01  +
Coupling states LEAK  + , ET  + , ROUTINE  +
Diseases Neurodegenerative  +
Has abstract Upregulation of the kynurenine pathway (KP
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<sup>+</sup>), 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.
ative stress and mitochondrial impairment.  +
Has editor [[Plangger M]]  +
Has info [https://www.ncbi.nlm.nih.gov/pubmed/30666558 PMID: 30666558]  +
Has publicationkeywords Kynurenine 3-monooxygenase  + , Kynurenine pathway  + , Mitochondrial dysfunction  + , Oxidative stress  +
Has title Castellano-Gonzalez G, Jacobs KR, Don E, C
Castellano-Gonzalez G, Jacobs KR, Don E, Cole NJ, Adams S, Lim CK, Lovejoy DB, Guillemin GJ (2019) Kynurenine 3-monooxygenase activity in human primary neurons and effect on cellular bioenergetics identifies new neurotoxic mechanisms. Neurotox Res 35:530-41.
otoxic mechanisms. Neurotox Res 35:530-41.  +
Instrument and method Oxygraph-2k  +
Mammal and model Human  +
MiP area Respiration  + , Pharmacology;toxicology  +
Pathways ROX  +
Preparation Intact cells  +
Stress Oxidative stress;RONS  +
Tissue and cell HEK  +
Was published in journal Neurotox Res +
Was published in year 2019  +
Was written by Castellano-Gonzalez G + , Jacobs KR + , Don E + , Cole NJ + , Lim CK + , Lovejoy DB + , Guillemin GJ + , Adams S* +
Categories Publications
Modification date
"Modification date" is a predefined property that corresponds to the date of the last modification of a subject and is provided by Semantic MediaWiki.
11:15:43, 14 August 2019  +
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