Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q
Anita Ayer,
Daniel J. Fazakerley,
Cacang Suarna,
Ghassan J. Maghzal,
Diba Sheipouri,
Kevin J. Lee,
Michelle C. Bradley,
Lucía Fernández-del-Rio,
Sergey Tumanov,
Stephanie MY. Kong,
Jelske N. van der Veen,
Andrian Yang,
Joshua W.K. Ho,
Steven G. Clarke,
David E. James,
Ian W. Dawes,
Dennis E. Vance,
Catherine F. Clarke,
René L. Jacobs,
Roland Stocker
Affiliations
Anita Ayer
Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia
Daniel J. Fazakerley
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
Cacang Suarna
Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia
Ghassan J. Maghzal
Victor Chang Cardiac Research Institute, Sydney, Australia
Diba Sheipouri
Victor Chang Cardiac Research Institute, Sydney, Australia
Kevin J. Lee
Victor Chang Cardiac Research Institute, Sydney, Australia
Michelle C. Bradley
Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States
Lucía Fernández-del-Rio
Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States
Sergey Tumanov
Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia
Stephanie MY. Kong
Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, Australia
Jelske N. van der Veen
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
Andrian Yang
Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia
Joshua W.K. Ho
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 Kong Science Park, Hong Kong SAR, China
Steven G. Clarke
Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States
David E. James
Charles Perkins Centre, School of Life and Environmental Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia
Ian W. Dawes
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
Dennis E. Vance
Department of Biochemistry, University of Alberta, Edmonton, Canada
Catherine F. Clarke
Department of Chemistry and Biochemistry, and the Molecular Biology Institute, University of California, Los Angeles, United States
René L. Jacobs
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
Roland Stocker
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, Sydney, Australia; Corresponding author. Heart Research Institute, 7 Eliza St Newtown, 2042, Australia.
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.
