Phosphatidylethanolamine Metabolism in Health and Disease

Abstract

Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways that produce PE, highlights the importance of this essential phospholipid. The CDP-ethanolamine and phosphatidylserine decarboxylase pathways occur in different subcellular compartments and are the main sources of PE in cells. Mammalian development fails upon ablation of either pathway. Once made, PE has diverse cellular functions that include serving as a precursor for phosphatidylcholine and a substrate for important posttranslational modifications, influencing membrane topology, and promoting cell and organelle membrane fusion, oxidative phosphorylation, mitochondrial biogenesis, and autophagy. The importance of PE metabolism in mammalian health has recently emerged following its association with Alzheimer's disease, Parkinson's disease, nonalcoholic liver disease, and the virulence of certain pathogenic organisms.

Keywords: Alzheimer's disease; CDP-ethanolamine; Parkinson's disease; autophagy; mitochondria; phosphatidylethanolamine; phosphatidylserine decarboxylase.

Figure 1

The glycerophospholipids. (A) Diagram of phosphatidylethanolamine structure. The spheres represent different atoms present in the phospholipid structure tan: carbon, red: oxygen, orange: phosphate, and blue: nitrogen (hydrogen atoms are not represented). (B) General glycerophospholipid structure. Fatty acids are linked to the glycerol backbone at the sn-1 and sn-2 positions while the phosphate headgroup is linked at the sn-3 position. Different variations of headgroups are shown (for cardiolipin, R indicates additional acyl groups attached at these positions).

Figure 2

PE biosynthetic pathways at the ER–mitochondria interface in yeast. (1) Base exchange pathway. In the biosynthesis of PS, head group exchange with PE is mediated by PSS2 in mammals. The reverse reaction can also synthesize PE from PS in small amounts. In yeast, calcium mediates base exchange between PS and PE through poorly understood mechanisms. (2) Acylation of lyso-PE to PE. Ale1p is an acyl transferase that facilitates the conversion of lyso-PE to PE. (3) CDP-ethanolamine pathway or Kennedy pathway. Phosphoethanolamine (Eth-P) is generated by phosphorylation of ethanolamine (Eth) by ethanolamine kinase (Ek1p) or through degradation of sphingolipids by Dpl1p. Phosphoethanolamine and CTP are metabolized by CTP:phosphoethanolamine cytidylyltransferase (Ect1p in yeast, ET in mammals) to generate CDP-ethanolamine (CDP-Eth), which with 1,2-diacylglycerol ethanolamine phosphotransferase (Ept1p in yeast, ETP in mammals) undergoes a condensation reaction with DAG to form the final product, PE. (4) Phosphatidylserine decarboxylase pathway. Upon its synthesis, PS is transported from the MAM of the ER to the OM of mitochondria until it reaches the IM where Psd1p is located. EMC and ERMES may facilitate transfer of PS to the OM. The OM and IM of mitochondria are tethered by mitochondrial contact site and cristae organizing system (MICOS) structures (please refer to text for mammalian proteins that also serve tethering functions). Alternatively, PS can be transferred to mitochondrial membranes through the yeast vacoule facilitated by v-CLAMP membrane tethers. In the enzymatic step, Psd1p decarboxylates PS to generate PE that is integrated in mitochondrial membranes or exported to other locations in the cell. PE generated by any of these pathways can be converted to PC through the action of PE methyltransferases (Pem1p/Pem2p in yeast or PEMT in mammals).

Figure 3

Atg8p lipidation in yeast. (A) Atg8p is proteolytically processed by the cysteine-protease Atg4p, which removes the C-terminal arginine residue and exposes a critical glycine that is recognized by Atg7p. Atg7p transfers Atg8p to Atg3p that together with the Atg12p–Atg5p protein complex conjugates Atg8p to PE. Atg8p is tethered via PE to membranes on the preautophagosomal structure (PAS) as it expands to the phagophore membrane. The phagophore membrane increases in size as it surrounds its cellular cargo to form a mature autophagosome. (B) When the autophagosome has reached its target size, Atg8p is cleaved at its terminal glycine residue by Atg4p. Similar mechanisms have been observed for LC3 lipidation using the ATG machinery in mammals.

Figure 4

Alzheimer's disease. Schematic representation of amyloidogenic and nonamyloidogenic processing of APP. (A) Under physiologic conditions, APP is processed by both the α- and β-secretases, each event followed by cleavage by γ-secretase, and an equilibrium exists in which Aβ aggregates do not accumulate. (B) However, when there is excess PE, β- and γ-secretase activity is increased, which shifts the equilibrium toward the amyloidogenic pathway thus driving the accumulation and aggregation of Aβ. (C) In contrast, when PE is limiting (i.e., psd1Δ yeast), α-secretase activity is increased thus promoting the nonamyloidogenic pathway. How PE mechanistically alters the activity of the assorted secretases is presently unclear. The thickness of the arrows indicates the relative activity of a particular enzyme. APP-α is a cleavage product of α-secretase; APP-β is a cleavage product of β-secretase.

Figure 5

Parkinson's disease. The role of α-synuclein at the MAM and how disturbances in this association impact cell function. (A) Under physiologic conditions, α-synuclein is natively unfolded and found primarily in the cytoplasm or associated with the plasma membrane, but a small fraction associates with the MAM where it supports full mitochondrial function. (B) Mutations that affect α-synuclein membrane association prevent its association with the MAM, drive its cytosolic accumulation and aggregation, and induce mitochondrial fragmentation. (C) When PE levels become limiting, α-synuclein accumulates at the MAM leading to ER stress and cytotoxicity. Relative activity is reflected by the thickness of the arrows. N, Nucleus; M, mitochondria; PM, plasma membrane.

Figure 6

PE:PC ratio in liver disease. (A) MDR2 is a PC-specific flippase that mediates the secretion of PC into bile. (B) Depletion of PC levels by ablating its synthesis via the PEMT pathway leads to an increase in the PE:PC ratio in hepatocyte membranes due to both a decrease in its synthesis as well as continued secretion by MDR2. A decrease in the levels of PC relative to PE results in leaky hepatocyte membranes causing cell lysis and subsequent tissue damage. (C) CDP-ethanolamine pathway in hepatocytes. (D) Upon deletion of CTP:phosphoethanolamine cytidylyltransferase in the CDP-ethanolamine pathway, the DAG that is normally used to generate CDP-ethanolamine accumulates and is instead consumed to form triglyceride (TG). Increased accumulation of triglycerides leads to the development of steatosis. EK, ethanolamine kinase.