Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
Anita Ayer,Anita Ayer,Daniel J. Fazakerley,Daniel J. Fazakerley,Cacang Suarna,Cacang Suarna,Ghassan J. Maghzal,Diba Sheipouri,Kevin J. Lee,Michelle C. Bradley,Lucía Fernández-del-Río,Sergey Tumanov,Sergey Tumanov,Stephanie M Y Kong,Stephanie M Y Kong,Jelske N. van der Veen,Andrian Yang,Andrian Yang,Joshua W. K. Ho,Steven Clarke,David E. James,Ian W. Dawes,Dennis E. Vance,Catherine F. Clarke,René L. Jacobs,Roland Stocker +25 more
Reads0
Chats0
TLDR
In this paper, a quantitative high-throughput method was developed to determine CoQ concentrations in yeast cells, which revealed 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.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.read more
Citations
More filters
Journal ArticleDOI
Recent advances in the metabolic pathways and microbial production of coenzyme Q
TL;DR: A review of the discovery of the CoQ pathway with a particular focus on its superstructuration and regulation is presented in this article , where the authors summarize the metabolic engineering strategies for overproduction of CoQ by microorganisms.
Journal ArticleDOI
The role of mitochondrial reactive oxygen species in insulin resistance
TL;DR: A review of the evidence linking mitochondrial reactive oxygen species generated within mitochondria with insulin resistance in adipose tissue and skeletal muscle, two major insulin sensitive tissues, is presented in this paper .
Journal ArticleDOI
The role of mitochondrial reactive oxygen species in insulin resistance.
TL;DR: A review of the evidence linking mitochondrial reactive oxygen species generated within mitochondria with insulin resistance in adipose tissue and skeletal muscle, two major insulin sensitive tissues, is presented in this paper.
Journal ArticleDOI
Coenzyme Q biochemistry and biosynthesis.
RM Guerra,David J. Pagliarini +1 more
TL;DR: Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes and serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species and engages in cellular signaling and oxygen sensing as discussed by the authors .
Journal ArticleDOI
How plants synthesize coenzyme Q
TL;DR: Recently, significant advances have been made in understanding CoQ biosynthesis in plants and recent efforts to increase the CoQ content in plant foods have been discussed in this paper , which provides new insights into the diversity of coq biosynthetic pathways and the evolution of phototrophic eukaryotes.
References
More filters
Journal ArticleDOI
Functional Characterization of the S. cerevisiae Genome by Gene Deletion and Parallel Analysis
Elizabeth A. Winzeler,Daniel D. Shoemaker,Anna Astromoff,Hong Liang,Keith Anderson,Bruno André,Rhonda Bangham,Rocío Benito,Jef D. Boeke,Howard Bussey,Angela M. Chu,Carla Connelly,Karen Davis,Fred S. Dietrich,Sally Dow,Mohamed El Bakkoury,Françoise Foury,Stephen H. Friend,Erik Gentalen,Guri Giaever,Johannes H. Hegemann,Ted Jones,Michael T. Laub,Hong Liao,Nicole Liebundguth,David J. Lockhart,Anca Lucau-Danila,Marc Lussier,Nasiha M'Rabet,Patrice Menard,Michael Mittmann,Chai Pai,Corinne Rebischung,José L. Revuelta,Linda Riles,Christopher J. Roberts,Petra Ross-Macdonald,Bart Scherens,Michael Snyder,Sharon Sookhai-Mahadeo,Reginald Storms,Steeve Veronneau,Marleen Voet,Guido Volckaert,Teresa R. Ward,Robert W. Wysocki,Grace Yen,Kexin Yu,Katja Zimmermann,Peter Philippsen,Mark Johnston,Ronald W. Davis +51 more
TL;DR: A total of 6925 Saccharomyces cerevisiae strains were constructed, by a high-throughput strategy, each with a precise deletion of one of 2026 ORFs (more than one-third of the ORFs in the genome), finding that 17 percent were essential for viability in rich medium.
Journal ArticleDOI
The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.
Kirill Bersuker,Joseph M. Hendricks,Zhipeng Li,Leslie Magtanong,Breanna Ford,Peter H. Tang,Melissa A. Roberts,Bingqi Tong,Thomas J. Maimone,Roberto Zoncu,Michael C. Bassik,Daniel K. Nomura,Scott J. Dixon,James A. Olzmann +13 more
TL;DR: AFerroptosis suppressor protein 1 (FSP1) is identified as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway, and pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroPTosis-inducing chemotherapeutic agents.
Journal ArticleDOI
Phospholipid synthesis in a membrane fraction associated with mitochondria.
TL;DR: Fraction X in combination with mitochondria might be responsible for the observed compartmentalization of a serine-labeled pool of phospholipids previously identified and might be involved in the transfer of lipids between the endoplasmic reticulum and mitochondria.
Journal ArticleDOI
Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity
Suneng Fu,Ling Yang,Ping Li,Oliver Hofmann,Lee H. Dicker,Winston Hide,Xihong Lin,Steven M. Watkins,Alexander R. Ivanov,Goekhan S. Hotamisligil,Goekhan S. Hotamisligil +10 more
TL;DR: Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis is established.
Journal ArticleDOI
The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease.
Jelske N. van der Veen,John P. Kennelly,Sereana Wan,Jean E. Vance,Dennis E. Vance,René L. Jacobs +5 more
TL;DR: Data showing that changes in the PC and/or PE content of various tissues are implicated in metabolic disorders such as atherosclerosis, insulin resistance and obesity is highlighted.