Ayer 2021 Redox Biol
|Ayer A, Fazakerley DJ, Suarna C, Maghzal GJ, Sheipouri D, Lee KJ, Bradley MC, Fernández-Del-Rio L, Tumanov S, Kong SM, van der Veen JN, Yang A, Ho JWK, Clarke SG, James DE, Dawes IW, Vance DE, Clarke CF, Jacobs RL, Stocker R (2021) Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q. Redox Biol 46:102127.
Ayer Anita, Fazakerley Daniel J, Suarna Cacang, Maghzal Ghassan J, Sheipouri Diba, Lee Kevin J, Bradley Michelle C, Fernandez-Del-Rio Lucia, Tumanov Sergey, Kong Stephanie, 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 Rene L, Stocker Roland (2021) Redox Biol
Abstract: 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. • Keywords: Coenzyme Q, Insulin resistance, Mitochondria, PEMT, Reactive oxygen species, S-adenosylhomocysteine, S-adenosylmethionine • Bioblast editor: Plangger M • O2k-Network Lab: AU Sydney Kong S
Labels: MiParea: Respiration
Organism: Saccharomyces cerevisiae
Preparation: Intact organism
Coupling state: ROUTINE, ET