We want to explain some roles of phospholipid metabolism in physiological processes such as programmed cell death, autophagy, and secretion. Phosphatidylcholine (PtdCho) is the major phospholipid in cell membranes, but its implication in many aspects of physiology and pathology, some of them relevant to the nervous system, is just beginning to be unraveled.
MAIN RESEARCH LINES
1) Mec1.- Mechanisms of cell death associated with the inhibition of PtdCho synthesis
A variety of drugs inhibit PtdCho synthesis after their interaction with CTP: phosphocholine cytidylyltransferase (CCT), one of the three enzymes of the CDP-choline pathway, and this results in the induction of cell death. We are currently studying CHO-MT58 cells, which possess a mutated, thermosensitive CCTα enzyme. The process of cell death does not imply apoptotic mechanisms and apparently takes place with typical autophagic traits.
2) The biogenesis of lipid droplets and their role in cell survival
Lipid droplets (LD) are triglyceride and cholesteryl-ester-storing organelles, somehow similar to the big droplet of adipocytes, but found in virtually all cell types including neurons and astrocytes. LD is very dynamic organelles that appear in the cytosol when cells take up lipoproteins or free fatty acids from the medium. LD also appear in the absence of external lipid sources when cells are under stress: in this case, LD confer resistance to stress, and triglycerides contained in LD derive from the cell's own membrane phospholipids in a process depending on Group VIA phospholipase A2 (iPLA2-VIA). We have also identified Group IVA phospholipase A2 (cPLA2α) as a necessary enzyme for the biogenesis of LD after triglycerides synthesized in the ER. We are currently exploring mechanisms up- and downstream of cPLA2α accounting for LD biogenesis under different physiological situations.
• Agnetta L, Bermudez M, Riefolo F, Matera C, Claro E, Messerer R, et al.
Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties.
J Med Chem. 2019 Mar 28; 62(6):3009–20.
• Riefolo F, Matera C, Garrido-Charles A, Gomila AMJ, Sortino R, Agnetta L, et al.
Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist.
J Am Chem Soc. 2019 May;141(18):7628–36.
• Eraso-Pichot A, Brasó-Vives M, Golbano A, Menacho C, Claro E, Galea E, et al.
GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes.
Glia. 2018 Aug;66(8):1724–35.
• Cordón-Barris L, Pascual-Guiral S, Yang S, Giménez-Llort L, Lope-Piedrafita S, Niemeyer C, et al.
Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors.
Mol Cell Biol. 2016 Dec;36(23):2967–82.
• Cabodevilla AG, Sánchez-Caballero L, Nintou E, Boiadjieva VG, Picatoste F, Gubern A, Claro E. Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fatty acids.
J Biol Chem. 2013 Sep 27;288(39):27777-88.Epub 2013
• A. Gubern, M. Barceló-Torns, D. Barneda, R. Masgrau, F. Picatoste, J. Casas, J. Balsinde, M.A. Balboa, E. Claro. Lipid droplet biogenesis induced by stress involves triacylglycerol synthesis that depends on Group VIA phospholipase A2.
J Biol Chem. 2009;284(9):5697-708.
• A. Gubern, M. Barceló-Torns, D. Barneda, J.M. López, R. Masgrau, F. Picatoste, C.E. Chalfant, J. Balsinde, M.A. Balboa, E. Claro. JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of Group IVA phospholipase A2.
J Biol Chem. 2009;284(47):32359-69.
• A. Gubern, J. Casas, M. Barceló-Torns, D. Barneda, X. de la Rosa, R. Masgrau, F. Picatoste, J. Balsinde, M.A. Balboa, E. Claro. Group IVA phospholipase A2 is necessary for the biogenesis of lipid droplets.
J Biol Chem. 2008;283(41):27369-82.