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dc.contributor.authorUgun-Klusek, Aslihan
dc.contributor.authorTheodosi, Theodosis S
dc.contributor.authorFitzgerald, Julia C
dc.contributor.authorBurté, Florence
dc.contributor.authorUfer, Christoph
dc.contributor.authorBoocock, David J
dc.contributor.authorYu Wai Man, Patrick
dc.contributor.authorBedford, Lynn
dc.contributor.authorBillett, E Ellen
dc.date.accessioned2018-12-08T00:31:35Z
dc.date.available2018-12-08T00:31:35Z
dc.date.issued2019-01
dc.identifier.issn2213-2317
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286552
dc.description.abstractMonoamine oxidases (MAOs) are located on the outer mitochondrial membrane and are drug targets for the treatment of neurological disorders. MAOs control the levels of neurotransmitters in the brain via oxidative deamination and contribute to reactive oxygen species (ROS) generation through their catalytic by-product H2O2. Increased ROS levels may modulate mitochondrial function and mitochondrial dysfunction is implicated in a vast array of disorders. However, the downstream effects of MAO-A mediated ROS production in a neuronal model has not been previously investigated. In this study, using MAO-A overexpressing neuroblastoma cells, we demonstrate that higher levels of MAO-A protein/activity results in increased basal ROS levels with associated increase in protein oxidation. Increased MAO-A levels result in increased Lysine-63 linked ubiquitination of mitochondrial proteins and promotes autophagy through Bcl-2 phosphorylation. Furthermore, ROS generated locally on the mitochondrial outer membrane by MAO-A promotes phosphorylation of dynamin-1-like protein, leading to mitochondrial fragmentation and clearance without complete loss of mitochondrial membrane potential. Cellular ATP levels are maintained following MAO-A overexpression and complex IV activity/protein levels increased, revealing a close relationship between MAO-A levels and mitochondrial function. Finally, the downstream effects of increased MAO-A levels are dependent on the availability of amine substrates and in the presence of exogenous substrate, cell viability is dramatically reduced. This study shows for the first time that MAO-A generated ROS is involved in quality control signalling, and increase in MAO-A protein levels leads to a protective cellular response in order to mediate removal of damaged macromolecules/organelles, but substrate availability may ultimately determine cell fate. The latter is particularly important in conditions such as Parkinson's disease, where a dopamine precursor is used to treat disease symptoms and highlights that the fate of MAO-A containing dopaminergic neurons may depend on both MAO-A levels and catecholamine substrate availability.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCell Line, Tumor
dc.subjectMitochondria
dc.subjectHumans
dc.subjectNeuroblastoma
dc.subjectReactive Oxygen Species
dc.subjectCaspases
dc.subjectMonoamine Oxidase
dc.subjectProto-Oncogene Proteins c-bcl-2
dc.subjectProteome
dc.subjectFluorescent Antibody Technique
dc.subjectImmunohistochemistry
dc.subjectProteomics
dc.subjectCell Survival
dc.subjectGene Expression
dc.subjectOxidation-Reduction
dc.subjectOxidative Stress
dc.subjectPhosphorylation
dc.subjectModels, Biological
dc.subjectAutophagy
dc.titleMonoamine oxidase-A promotes protective autophagy in human SH-SY5Y neuroblastoma cells through Bcl-2 phosphorylation.
dc.typeArticle
prism.endingPage181
prism.publicationDate2019
prism.publicationNameRedox Biol
prism.startingPage167
prism.volume20
dc.identifier.doi10.17863/CAM.33862
dcterms.dateAccepted2018-10-06
rioxxterms.versionofrecord10.1016/j.redox.2018.10.003
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-01
dc.contributor.orcidYu Wai Man, Patrick [0000-0001-7847-9320]
dc.identifier.eissn2213-2317
rioxxterms.typeJournal Article/Review


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International