title: Mapping the Human Platelet Lipidome Reveals Cytosolic Phospholipase A2 as a Regulator of Mitochondrial Bioenergetics during Activation.
abstract: Human platelets acutely increase mitochondrial energy generation following stimulation. Herein, a lipidomic circuit was uncovered whereby the substrates for this are exclusively provided by cPLA2, including multiple fatty acids and oxidized species that support energy generation via β-oxidation. This indicates that acute lipid membrane remodeling is required to support energetic demands during platelet activation. Phospholipase activity is linked to energy metabolism, revealing cPLA2 as a central regulator of both lipidomics and energy flux. Using a lipidomic approach (LipidArrays), we also estimated the total number of lipids in resting, thrombin-activated, and aspirinized platelets. Significant diversity between genetically unrelated individuals and a wealth of species was revealed. Resting platelets demonstrated ∼5,600 unique species, with only ∼50% being putatively identified. Thrombin elevated ∼900 lipids >2-fold with 86% newly appearing and 45% inhibited by aspirin supplementation, indicating COX-1 is required for major activation-dependent lipidomic fluxes. Many lipids were structurally identified. With ∼50% of the lipids being absent from databases, a major opportunity for mining lipids relevant to human health and disease is presented.
authors.affiliation: Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Slatter
authors.affiliation: Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Maceler
authors.initials: M
authors.lastname: Aldrovandi
authors.affiliation: Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Connor
authors.affiliation: School of Computer Science and Informatics, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allen
authors.affiliation: School of Computer Science and Informatics, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brasher
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Sven
authors.initials: S
authors.lastname: Mecklemann
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Saranya
authors.initials: S
authors.lastname: Ravi
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
authors.affiliation: Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: o-donnellvb@cardiff.ac.uk.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
mesh_terms: D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015777:Eicosanoids; D005227:Fatty Acids; D010743:Phospholipids; D054510:Phospholipases A2, Cytosolic; D013917:Thrombin; D001241:Aspirin