Mapping the Human Platelet Lipidome Reveals Cytosolic Phospholipase A2 as a Regulator of Mitochondrial Bioenergetics during Activation

Abstract

SummaryHuman 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.

Platelets from pulmonary hypertension patients show increased mitochondrial reserve capacity

“…*P < 0.01. A recent study demonstrated that platelet activation induced by thrombin leads to increased platelet FAO and lipid mobilization through the actions of cytosolic phospholipase A 2 (40). Although our data show upregulated FAO in PH platelets, we did not observe a significant increase in platelet activation markers.…”

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…3). This eicosanoid has been associated with peroxisome deficiency disorders and chronic kidney disease (Mayatepek et al, 1993; Zhang et al, 2016); more recently it was detected in resting human platelets, but not in thrombin activated platelets (Slatter et al, 2016). While leukotriene B4 (LTB4) is an inflammatory molecule and chemoattractant that mediates the migration of neutrophils induced by heme (Monteiro et al, 2011), omega-oxidation is the main pathway used by human neutrophils to catabolize LTB4, regulating the inflammatory profiles of these cells (Shak and Goldstein, 1984).…”

Mitochondrial network responses in oxidative physiology and disease

“…Protein-lipid interactions vary in specificity, with some protein structures requiring specific cardiolipins [24]. The recent study of human platelet lipidomics showed that mitochondrial lipidome is changed acutely in association with phospholipase and COX-1-dependent increased energy metabolism upon platelet activation [25], supporting the critical role for mitochondrial protein-lipid networks in controlling inflammation. Informative relationships of proteins, lipids and other macromolecules can be visualized with such an approach.…”