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Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.

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cam.issuedOnline2021-09-08
dc.contributor.authorAyer, Anita
dc.contributor.authorFazakerley, Daniel J
dc.contributor.authorSuarna, Cacang
dc.contributor.authorMaghzal, Ghassan J
dc.contributor.authorSheipouri, Diba
dc.contributor.authorLee, Kevin J
dc.contributor.authorBradley, Michelle C
dc.contributor.authorFernández-Del-Rio, Lucía
dc.contributor.authorTumanov, Sergey
dc.contributor.authorKong, Stephanie My
dc.contributor.authorvan der Veen, Jelske N
dc.contributor.authorYang, Andrian
dc.contributor.authorHo, Joshua WK
dc.contributor.authorClarke, Steven G
dc.contributor.authorJames, David E
dc.contributor.authorDawes, Ian W
dc.contributor.authorVance, Dennis E
dc.contributor.authorClarke, Catherine F
dc.contributor.authorJacobs, René L
dc.contributor.authorStocker, Roland
dc.contributor.orcidFazakerley, Daniel [0000-0001-8241-2903]
dc.date.accessioned2021-11-25T17:28:52Z
dc.date.available2021-11-25T17:28:52Z
dc.date.issued2021-10
dc.description.abstractMitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.78626
dc.identifier.eissn2213-2317
dc.identifier.issn2213-2317
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331179
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.redox.2021.102127
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCoenzyme Q
dc.subjectInsulin resistance
dc.subjectMitochondria
dc.subjectPEMT
dc.subjectReactive oxygen species
dc.subjectS-adenosylhomocysteine
dc.subjectS-adenosylmethionine
dc.subjectAnimals
dc.subjectGenetic Testing
dc.subjectMice
dc.subjectMitochondrial Diseases
dc.subjectOxidation-Reduction
dc.subjectPhosphatidylethanolamine N-Methyltransferase
dc.subjectPhospholipids
dc.subjectUbiquinone
dc.titleGenetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
dc.typeArticle
dcterms.dateAccepted2021-09-04
prism.publicationDate2021
prism.publicationNameRedox Biol
prism.startingPage102127
prism.volume46
rioxxterms.licenseref.startdate2021-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.redox.2021.102127

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