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Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
Ayer, Anita; Fazakerley, Daniel J; Suarna, Cacang; Maghzal, Ghassan J; Sheipouri, Diba; Lee, Kevin J; Bradley, Michelle C; Fernández-Del-Rio, Lucía; Tumanov, Sergey; Kong, Stephanie My; van der Veen, Jelske N; Yang, Andrian; Ho, Joshua W K; Clarke, Steven G; James, David E; Dawes, Ian W; Vance, Dennis E; Clarke, Catherine F; Jacobs, René L; Stocker, Roland.
Afiliación
  • Ayer A; Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Fazakerley DJ; Charles Perkins Centre, School of Life and Environmental Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia; Metabolic Research Laboratory, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
  • Suarna C; Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Maghzal GJ; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Sheipouri D; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Lee KJ; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Bradley MC; Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States.
  • Fernández-Del-Rio L; Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States.
  • Tumanov S; Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • Kong SM; Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia.
  • van der Veen JN; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada.
  • Yang A; Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
  • Ho JWK; Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China; Laboratory for Data Discovery for Health, Hong Ko
  • Clarke SG; Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States.
  • James DE; Charles Perkins Centre, School of Life and Environmental Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia.
  • Dawes IW; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
  • Vance DE; Department of Biochemistry, University of Alberta, Edmonton, Canada.
  • Clarke CF; Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States.
  • Jacobs RL; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada.
  • Stocker R; Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; School of Life and Environmental Sciences, The University of Sydney, Syd
Redox Biol ; 46: 102127, 2021 10.
Article en En | MEDLINE | ID: mdl-34521065
Mitochondrial 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ubiquinona / Enfermedades Mitocondriales Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals Idioma: En Revista: Redox Biol Año: 2021 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ubiquinona / Enfermedades Mitocondriales Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals Idioma: En Revista: Redox Biol Año: 2021 Tipo del documento: Article País de afiliación: Australia