Review
From zero to six double bonds: phospholipid unsaturation and organelle function

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Highlights

  • Membrane bound organelles differ by the acyl chain profile of their phospholipids.

  • Monounsaturated phospholipids and curvature cooperate to create lipid-packing defects.

  • Polyunsaturated phospholipids have no intrinsic shape and correct lipid-packing defects.

  • Polyunsaturated phospholipids soften fast mechanical stresses (e.g., curvature).

Cellular phospholipids (PLs) differ by the nature of their polar heads as well as by the length and unsaturation level of their fatty acyl chains. We discuss how the ratio between saturated, monounsaturated, and polyunsaturated PLs impacts on the functions of such organelles as the endoplasmic reticulum, synaptic vesicles, and photoreceptor discs. Recent experiments and simulations suggest that polyunsaturated PLs respond differently to mechanical stress, including membrane bending, than monounsaturated PLs owing to their unique conformational plasticity. These findings suggest a rationale for PL acyl chain remodeling by acyltransferases and a molecular explanation for the importance of a balanced fatty acid diet.

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).

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