Trends in Cell Biology
ReviewFrom zero to six double bonds: phospholipid unsaturation and organelle function
Section snippets
Fatty acyl chain diversity: the dark face of cellular membranes
The lipid composition of cellular membranes varies significantly among organisms, tissues, and organelles, and our knowledge of this diversity has greatly increased thanks to progress in organelle fractionation, lipid analysis, notably mass spectroscopy, and the identification and characterization of most enzymes responsible for lipid synthesis 1, 2, 3, 4, 5. However, our understanding of the roles of the various lipids that coexist in biological membranes has not improved as fast. Hundreds of
Biochemical pathways promoting PL acyl chain diversity
The acyl chain diversity of PLs results from several processes, from diet sources to complex reactions where fatty acids are elongated, desaturated, transported, and eventually esterified into PLs (Figure 1A) 15, 16.
Almost all organisms contain a Δ9 desaturase, which introduces a double bond in the middle of the acyl chain, thus producing monounsaturated fatty acids from saturated ones (e.g., C18:0 > C18:1-n9). By contrast, the ability to add additional double bonds is not universal. Some plants
Examples of PL fatty acyl chain gradients
In mammalian cells, there is a gradual enrichment of saturated PL species at the expense of monounsaturated species along the organelles of the secretory pathway (ER > Golgi > plasma membrane) [8]. This subcellular gradient, which parallels main membrane traffic routes, also exists in yeast and results from a change in the esterified acyl chains of PE and PS [9] (Figure 1B).
Recent advances in lipid imaging by mass spectrometry reveal another striking acyl chain gradient (Figure 1C). In neuronal
Influence of PL acyl chains on protein synthesis and folding at the ER
The ER is the organelle for the biosynthesis and folding of transmembrane and luminal proteins. To maintain the correct balance between ER client protein load and folding capacity, cells have developed a pathway known as the unfolded protein response (UPR) 25, 26. The UPR is controlled by integral protein sensors, such as inositol-requiring enzyme 1 (IRE1) and protein kinase-like ER kinase (PERK) 25, 26, which are maintained in an inactive monomeric form by the interaction of their luminal
PL monounsaturation, membrane curvature, and protein adsorption
How the ratio between saturated and monounsaturated PLs controls transmembrane helices oligomerization at the ER remains elusive, although several mechanisms have been proposed [49]. By contrast, the monounsaturated/saturated PL ratio has another impact that is more straightforward to rationalize. Introducing monounsaturated PLs at the expense of saturated ones facilitates the membrane adsorption of several cytosolic proteins acting on the ER or ER-derived organelles such as autophagosomes or
Molecular dynamics simulations of lipid-packing defects
Although the scheme of Figure 2A is obviously naïve because lipids are not stiff, addressing the molecular organization of lipids in bilayers of different compositions and geometries is experimentally very difficult. To overcome these limitations, and to investigate microscopic properties of lipid assemblies, a powerful methodology is molecular dynamics simulations (Box 2), a computational approach that allows investigating the behavior of lipid membranes with atomic-level resolution. Using
PL polyunsaturation in phototransduction
Phototransduction, one of the best-characterized transduction cascades, occurs in a membrane rich in ω3 lipids. In the photoreceptor discs, DHA (22:6-n3) accounts for 50% of the PL acyl chains [62]. The proteins involved in phototransduction, namely the light receptor rhodopsin, the G protein transducin, and its effector, a cGMP phosphodiesterase, have been reconstituted into artificial liposomes. This reductionist approach revealed that replacing C16:0-C18:1 by C18:0-C22:6 PLs increases the
Biophysical measurements of the behavior of polyunsaturated PLs in bilayers
Studies on phototransduction have stimulated detailed biophysical studies on the behavior of polyunsaturated PLs in model membranes 65, 66. Neutron and X-ray diffraction as well as NMR measurements revealed that, in bilayers containing mixed acyl chain PLs (e.g., C16:0-C18:1 vs C18:0-C22:6), polyunsaturated acyl chains occupy more space at the water interface than saturated or monounsaturated chains, despite polyunsaturated acyl chains being generally longer (e.g., C22:6 vs C18:1). This
Polyunsaturated PLs as contortionists
Polyunsaturated acyl chains were initially considered to be more rigid than saturated acyl chains because a C=C bond cannot rotate about its axis. In polyunsaturated acyl chains, however, the C=C bonds are systematically flanked by two saturated bonds. Calculations and simulations revealed that this regular pattern of one non-rotating and two rotating bonds decreases the energy of rotation about the saturated carbons 32, 67, 68 (Figure 3A). The exceptional flexibility of polyunsaturated acyl
PL polyunsaturation in synaptic functions
Synaptic vesicles (SV) deliver neurotransmitters in the synaptic cleft in response to action potentials. Although the abundance of polyunsaturated PLs is a remarkable feature of SVs [11] (Figure 1C), studies on the role of lipids in the cycling of these organelles have focused on other aspects [73]. In this section we present a hypothesis for the role of polyunsaturated PLs in SVs, which was inspired by observations made years ago but was formulated only recently [74].
In 1986, electron
Concluding remarks
Simple organisms contain only saturated and monounsaturated lipids, highlighting a fundamental role of the monounsaturated/saturated ratio for elementary functions. This ratio ranges from low values in membranes with a protective barrier function (apical membrane of epithelial cells, lung surfactant) [1], to high values in membranes with a biosynthetic function, as exemplified by the ER (Figure 1B). The evolutionary pressure for the conservation of Δ9 desaturase and the resulting selection of
Acknowledgments
Work in the laboratory of B.A. is supported by the CNRS, the European Research Council (advanced grant 268888), and the Agence Nationale de la Recherche (ANR-11-LABX-0028-01).
References (107)
- et al.
Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity
Dev. Cell
(2012) Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo
Cell Metab.
(2014)Polyunsaturated fatty acid synthesis: what will they think of next?
Trends Biochem. Sci.
(2002)Molecular anatomy of a trafficking organelle
Cell
(2006)Axonal gradient of arachidonic acid-containing phosphatidylcholine and its dependence on actin dynamics
J. Biol. Chem.
(2012)- et al.
Acyl-CoA:lysophospholipid acyltransferases
J. Bio. Chem.
(2009) Uneven distribution of desmosterol and docosahexaenoic acid in the heads and tails of monkey sperm
J. Lipid Res.
(1998)Dividing cells regulate their lipid composition and localization
Cell
(2014)P53 mutations change phosphatidylinositol acyl chain composition
Cell Rep.
(2015)Decrease in membrane phospholipid unsaturation induces unfolded protein response
J. Biol. Chem.
(2010)
Structure–activity relationships influencing lipid-induced changes in eIF2alpha phosphorylation and cell viability in BRIN-BD11 cells
FEBS Lett.
Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death
J. Lipid Res.
Enrichment of endoplasmic reticulum with cholesterol Inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages
J. Biol. Chem.
A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS)
Arch. Biochem. Biophys.
Inhibition of protein translocation across the endoplasmic reticulum membrane by sterols
J. Biol. Chem.
Ca2+ signaling and calcium binding chaperones of the endoplasmic reticulum
Cell Calcium
A lipid E-MAP identifies Ubx2 as a critical regulator of lipid saturation and lipid bilayer stress
Mol. Cell
Stearoyl-CoA desaturase 1 activity is required for autophagosome formation
J. Biol. Chem.
Mechanism of membrane curvature sensing by amphipathic helix containing proteins
Biophys. J.
Conical lipids in flat bilayers induce packing defects similar to that induced by positive curvature
Biophys. J.
Amphipathic lipid packing sensor motifs: probing bilayer defects with hydrophobic residues
Biophys. J.
A reinvestigation of the fatty acid content of bovine, rat and frog retinal rod outer segments
Exp. Eye Res.
Optimization of receptor-G protein coupling by bilayer lipid composition I: kinetics of rhodopsin-transducin binding
J. Biol. Chem.
Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency
J. Biol. Chem.
Molecular order and dynamics in bilayers consisting of highly polyunsaturated phospholipids
Biophys. J.
Evidence for specificity in lipid-rhodopsin interactions
J. Biol. Chem.
Contribution of membrane elastic energy to rhodopsin function
Biophys. J.
Greasing the synaptic vesicle cycle by membrane lipids
Trends Cell Biol.
Effects of polyunsaturated fatty acids and hormones on synaptogenesis in serum-free medium cultures of mouse fetal hypothalamic cells
Neuroscience
Effect of chain length and unsaturation on elasticity of lipid bilayers
Biophys. J.
Molecular mechanisms of presynaptic membrane retrieval and synaptic vesicle reformation
Neuron
Clathrin/AP-2 mediate synaptic vesicle reformation from endosome-like vacuoles but are not essential for membrane retrieval at central synapses
Neuron
Phospholipids that contain polyunsaturated fatty acids enhance neuronal cell mechanics and touch sensation
Cell Rep.
Sensing pressure with ion channels
Trends Neurosci.
LET-767 is required for the production of branched chain and long chain fatty acids in Caenorhabditis elegans
J. Biol. Chem.
Quantifying the differential effects of DHA and DPA on the early events in visual signal transduction
Chem. Phys. Lipids
Membrane lipidome of an epithelial cell line
Proc. Natl. Acad. Sci. U.S.A.
Lipidomics: analysis of the lipid composition of cells and subcellular organelles by electrospray ionization mass spectrometry
Annu. Rev. Biochem.
Lipid landscapes and pipelines in membrane homeostasis
Nature
Membrane recognition by phospholipid-binding domains
Nat. Rev. Mol. Cell Biol.
Phospholipid class and fatty acid composition of golgi apparatus isolated from rat liver and comparison with other cell fractions
Biochemistry
Electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis of the lipid molecular species composition of yeast subcellular membranes reveals acyl chain-based sorting/remodeling of distinct molecular species en route to the plasma membrane
J. Cell Biol.
Mechanisms of action of docosahexaenoic acid in the nervous system
Lipids
Essential fatty acids: the work of George and Mildred Burr
J. Biol. Chem.
Polyunsaturated fatty acids and their metabolites in brain function and disease
Nat. Rev. Neurosci.
Generation of membrane diversity by lysophospholipid acyltransferases
J. Biochem.
Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans
Proc. Natl. Acad. Sci. U.S.A.
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
Nature
The physical state of lipid substrates provides transacylation specificity for tafazzin
Nat. Chem. Biol.
Arachidonoyl-phosphatidylcholine oscillates during the cell cycle and counteracts proliferation by suppressing Akt membrane binding
Proc. Natl. Acad. Sci. U.S.A.
Cited by (151)
Lipid droplets control mitogenic lipid mediator production in human cancer cells
2023, Molecular MetabolismLPGAT1/LPLAT7 regulates acyl chain profiles at the sn-1 position of phospholipids in murine skeletal muscles
2023, Journal of Biological ChemistryMembrane lipid remodeling modulates γ-secretase processivity
2023, Journal of Biological Chemistry