The expanding organelle lipidomes: current knowledge and challenges

Abstract

Lipids in cell membranes and subcellular compartments play essential roles in numerous cellular processes, such as energy production, cell signaling and inflammation. A specific organelle lipidome is characterized by lipid synthesis and metabolism, intracellular trafficking, and lipid homeostasis in the organelle. Over the years, considerable effort has been directed to the identification of the lipid fingerprints of cellular organelles. However, these fingerprints are not fully characterized due to the large variety and structural complexity of lipids and the great variability in the abundance of different lipid species. The process becomes even more challenging when considering that the lipidome differs in health and disease contexts. This review summarizes the information available on the lipid composition of mammalian cell organelles, particularly the lipidome of the nucleus, mitochondrion, endoplasmic reticulum, Golgi apparatus, plasma membrane and organelles in the endocytic pathway. The lipid compositions of extracellular vesicles and lamellar bodies are also described. In addition, several examples of subcellular lipidome dynamics under physiological and pathological conditions are presented. Finally, challenges in mapping organelle lipidomes are discussed.

Keywords: Cellular organelles; Lipidomics; Lipids; Mass spectrometry; Subcellular fractionation.

Fig. 1

Schematic representation of the main lipid classes, including one example per class, as characterized by the LIPID MAPS consortium

Fig. 2

Basic structure of glycerophospholipids. Those with either ester or ether versions, as well as the most common headgroups, are presented

Fig. 3

Schematic representation of different sphingolipids. a Ceramide is the building block of more complex sphingolipids. b Sphingomyelin is one of the most common sphingolipids in mammalian cells. c Examples of ganglioside headgroups. Gangliosides are glycosphingolipids with a ceramide backbone and headgroups with different sugar unit combinations. Blue circle: glucose; yellow circle: galactose; yellow square: N-acetylgalactosamine; and red diamond: N-acetylneuraminic acid

Fig. 4

Lipid composition affects organelle function, dynamics and integrity. a The composition of fatty acyl chains and polar headgroups in membrane phospholipids determine biophysical membrane properties, such as packing, bending and fluidity. b Lipids control protein binding to organelles. The composition of the hydrophobic lipid droplet core determines the affinity of amphipathic helix-containing proteins for the organelle (not to membrane bilayers) or to subsets of cellular lipid droplets with a specific oil composition. c Phospholipase A₂ (PLA₂) enzyme releases polyunsaturated fatty acids (PUFAs) from membrane phospholipids. PUFAs are converted into bioactive lipid mediators, such as eicosanoids, via various oxygenase enzymes, including lipoxygenases (LOXs) and cyclooxygenases (COXs). d The proportion of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs in membrane phospholipids is crucial to membrane and organelle function and integrity. Excess SFAs may cause endoplasmic reticulum stress, and excess PUFAs can be oxidized into toxic lipid peroxides that can cause ferroptotic cell death. Both stress-producing processes are mitigated by MUFAs

Fig. 5

Main lipid-related characteristics of cellular compartments in mammalian cells. The figure outlines the main lipid-related characteristic of the nucleus, endoplasmic reticulum, Golgi apparatus, plasma membrane, organelles of the endosomal pathway, mitochondria, lipid droplets, lamellar bodies and exosomes. Figure created with BioRender.com. BMP bis(monoacylglyceryl)phosphate. Chol, cholesterol, CL cardiolipin, GSL glycosphingolipids, PC phosphatidylcholine, PE phosphatidylethanolamine, PG phosphatidylglycerol, PI phosphatidylinositol, PI3P phosphatidylinositol 3-phosphate, PI(3,5)P2 phosphatidylinositol 3,5-bisphosphate, PI4P phosphatidylinositol 4-phosphate, PI(4,5)P2 phosphatidylinositol 4,5-bisphosphate, PL phospholipids, PS phosphatidylserine, SM sphingomyelin, TG triacylglycerol. The figure is based on the information and the references included in the paper

Fig. 6

Schematic representation of a typical subcellular fractionation protocol with tissues and cell cultures. The approximate centrifugation force (g) used for fractionation of subcellular compartments via differential and density gradient centrifugation is shown at the top of the figure. For extracellular vesicles, sequential centrifugation is used. Notably, EVs can be isolated from tissue. CYT cytoplasm, ER endoplasmic reticulum, EV extracellular vesicle, GA Golgi apparatus, MAM mitochondrion-associated membrane, MITO mitochondria, NUC nucleus, PAM plasma membrane-associated membranes, PM plasma membrane