Lipid map of the mammalian cell

Abstract

Technological developments, especially in mass spectrometry and bioinformatics, have revealed that living cells contain thousands rather than dozens of different lipids [for classification and nomenclature, see Fahy et al. (Fahy et al., 2009)]. Now, the resulting questions are what is the relevance of each of these unique molecules for the cell and how do cells use lipids for their vital functions? The answer requires an integrative approach – cellular lipidomics – which addresses first the distribution of all lipids between the various organelle membranes and then their local organization within each membrane. To understand lipid homeostasis and its dynamics, one has to study the localized metabolism of lipids, their transport within and between the various membranes, and the sensors and effectors that govern these processes. In terms of function, above all, we need to understand the physical behavior of complex lipid mixtures and their effect on local protein structure, organization and function. Finally, in the course of evolution, many lipids and lipid metabolites have acquired key functions in the signaling networks that wire the cell, by binding to cognate receptors and by recruiting proteins to specific membranes. The accompanying poster describes the lipid content of the various organelle membranes, illustrates lipid localization and dynamics in various subcellular locations, and explains the structure of lipids and their biosynthetic pathways. Below, we highlight additional issues that are important in lipid cell biology, and aim to provide a framework and a timely update for lipid systems biology.Bacteria, archaea and eukaryotes share glycerol as the backbone of most of their lipids. The typical bacterial phospholipids are phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and cardiolipin (CL), which are also found in eukaryotes. PG and CL are synthesized in and confined to mitochondria (see Poster). Mitochondria also harbor the (bacterial) enzyme PS-decarboxylase (PSD), which synthesizes half of the cellular PE. Phosphatidylcholine (PC) and phosphatidylinositol (PI) are the other major eukaryotic glycerophospholipids. Owing to its two fatty acyl chains and a large polar head, PC has a cylindrical shape. Because the entropy is highest when the lipid tails are turned away from water and water molecules have maximum freedom (the ‘hydrophobic effect’), PC molecules assemble into a bilayer. The typical PC carries one saturated and one unsaturated chain. It yields a fluid (‘liquid crystalline’) membrane with many characteristics of biomembranes. However, biomembranes typically contain five to ten major lipid classes (see Poster), which are needed for processes such as vesicle fusion and fission, membrane sorting and signal transduction.Most PE molecules found in biological membranes are cone shaped and don't form lipid bilayers by themselves. The non-bilayer propensity of PE is essential for the functional embedding of membrane proteins and for processes such as membrane fusion and fission. Under conditions of charge neutralization (divalent cations or high salt), mitochondrial CL also acquires a preference for a non-bilayer configuration. Inactivation of CL synthase and mitochondrial PSD in yeast is synthetically lethal (Gohil et al., 2005), indicating a requirement for mitochondrial non-bilayer lipids. The non-bilayer propensity of PE and CL depends on the length and level of unsaturation of their acyl chains. The acyl chain composition is modulated by acyl chain exchange, which is catalyzed by remodeling enzymes. The new developments in mass spectrometry have enabled us to monitor lipid remodeling in living cells (de Kroon, 2007) and also allowed rapid progress in the area of ether lipids. Up to 50% of glycerolipids contain ether-linked chains, but their functions remain largely unknown (Lessig and Fuchs, 2009).In addition to the glycerol-based phospholipids, eukaryotes invariably possess sphingolipids and sterols. Sphingolipids usually contain a long to very long saturated fatty acid (C16–C32) with an amide linkage to the sphingoid base (Poster). Variations such as C2-hydroxylation and C15-unsaturation are not uncommon. Sphingolipids generally adopt a solid gel phase, but are fluidized by sterols, which preferentially interact with them in the membrane. Sphingolipids and sterols are enriched in the plasma membrane and in endosomes. They render these membranes exceptionally sturdy. PC and PI are enriched in the endoplasmic reticulum (ER) [see Poster; diameters reflect contribution to total cellular lipid; calculated from Zambrano et al. (Zambrano et al., 1975) and Griffiths et al. (Griffiths et al., 1989)]. Similar to the bacterial membrane, the thin and flexible ER is involved in the insertion of membrane and secretory proteins. In addition to the differences between organelles, the two leaflets of (post-)Golgi membrane bilayers also have different lipid compositions