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

TitleGenetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q
Authors
KeywordsCoenzyme Q
Mitochondria
PEMT
Insulin resistance
S-adenosylmethionine
S-adenosylhomocysteine
Reactive oxygen species
Issue Date2021
PublisherElsevier: Creative Commons. The Journal's web site is located at http://www.journals.elsevier.com/redox-biology
Citation
Redox Biology, 2021, v. 46, article no. 102127 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/304556
ISSN
2023 Impact Factor: 10.7
2023 SCImago Journal Rankings: 3.008
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorAyer, A-
dc.contributor.authorFazakerley, DJ-
dc.contributor.authorSuarna, C-
dc.contributor.authorMaghzal, GJ-
dc.contributor.authorSheipouri, D-
dc.contributor.authorLee, KJ-
dc.contributor.authorBradley, MC-
dc.contributor.authorFernández-del-Rio, L-
dc.contributor.authorTumanov, S-
dc.contributor.authorKong, SMY-
dc.contributor.authorvan der Veen, JN-
dc.contributor.authorYang, A-
dc.contributor.authorHo, JWK-
dc.contributor.authorClarke, SG-
dc.contributor.authorJames, DE-
dc.contributor.authorDawes, IW-
dc.contributor.authorVance, DE-
dc.contributor.authorClarke, CF-
dc.contributor.authorJacobs, RL-
dc.contributor.authorStocker, R-
dc.date.accessioned2021-09-23T09:01:44Z-
dc.date.available2021-09-23T09:01:44Z-
dc.date.issued2021-
dc.identifier.citationRedox Biology, 2021, v. 46, article no. 102127-
dc.identifier.issn2213-2317-
dc.identifier.urihttp://hdl.handle.net/10722/304556-
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.languageeng-
dc.publisherElsevier: Creative Commons. The Journal's web site is located at http://www.journals.elsevier.com/redox-biology-
dc.relation.ispartofRedox Biology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCoenzyme Q-
dc.subjectMitochondria-
dc.subjectPEMT-
dc.subjectInsulin resistance-
dc.subjectS-adenosylmethionine-
dc.subjectS-adenosylhomocysteine-
dc.subjectReactive oxygen species-
dc.titleGenetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q-
dc.typeArticle-
dc.identifier.emailHo, JWK: jwkho@hku.hk-
dc.identifier.authorityHo, JWK=rp02436-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.redox.2021.102127-
dc.identifier.pmid34521065-
dc.identifier.pmcidPMC8435697-
dc.identifier.scopuseid_2-s2.0-85114717636-
dc.identifier.hkuros325594-
dc.identifier.volume46-
dc.identifier.spagearticle no. 102127-
dc.identifier.epagearticle no. 102127-
dc.identifier.isiWOS:000704257100002-
dc.publisher.placeNetherlands-

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