Phospholipid Membrane Transport and Associated Diseases

Abstract

Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to prevalent diseases such as atherosclerosis or non-alcoholic steatohepatitis (NASH) because they alter gene expression and induce cellular stress and apoptosis. One of the main sites of phospholipid synthesis is the endoplasmic reticulum (ER). ER association with other organelles through membrane contact sites (MCS) provides a close apposition for lipid transport. Additionally, an important advance in this small cytosolic gap are lipid transfer proteins (LTPs), which accelerate and modulate the distribution of phospholipids in other organelles. In this regard, LTPs can be established as an essential point within phospholipid circulation, as relevant data show impaired phospholipid transport when LTPs are defected. This review will focus on phospholipid function, metabolism, non-vesicular transport, and associated diseases.

Keywords: Mfn2; glycerophospholipid; lipid transport proteins; membrane contact sites; oxidized phospholipid.

Figure 1

Scheme of phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), cardiolipin (CL), and phosphatidylinositol (PI). Abbreviations: glycerol-3-Phosphate (G3P); glycerol-3-phosphate acyltransferase (GPAT); 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT); phosphatidic acid (PA); phosphatidic acid phosphatase (PAP); diacylglycerol (DAG); ethanolamine kinase (EK); phosphatidylserine synthase 2 (PSS2); phosphatidylserine synthase 1 (PSS1); CDP-choline:1,2-diacylglycerol cholinephosphotransferase (CTP); choline-phosphate cytidylyltransferase (CCT); choline kinase (CK); Cytidine diphosphate diacylglycerol synthetases 1/2 (CSD1/2); cytidine diphosphate diacylglycerol (CDP-DAG); (PIS); Mitochondrial translocator assembly and maintenance protein 41 (TAMM41); phosphatidylglycerophosphate (PGP); Protein Tyrosine Phosphatase Mitochondrial 1 (PTPMT1); phosphatidylglycerol (PG); cardiolipin synthase (CLS).

Figure 2

Representation of the phospholipid transport during phospholipase C (PLC) signaling. (a) Association between the endoplasmic reticulum (ER) and the plasma membrane (PM) is required in order to ensure high levels of phosphatidylinositol 4,5-biphosphate PI(4,5)P₂ which can drop quickly during PLC signaling. (b) Phosphatidylserine (PS) transport and PI(4,5)P₂ and phosphatidylinositol 4-phosphate PI4P removal. Oxysterol-binding protein (OSBP)-related protein 5/8 (ORP5/8) removes PI(4,5)P₂ and PI4P from the PM and transfers PS from the ER to PM in exchange, creating a gradient necessary for phosphatidylinositol (PI) transport. Abbreviations: PI4Kα, phosphatidylinositol 4-kinase; PI4P5K, phosphatidylinositol 4-phosphate 5-kinase; DGK, diacylglycerol kinase; PIS, phosphatidylinositol synthase; CDS, CDP-diacylglycerol synthase; synaptotagmins (E-Syts); the Phospholipid Transfer Protein C2CD2L (also known as TEM24 or C2CD2L); membrane-associated phosphatidylinositol transfer protein 1 (Nir2); phosphatidylinositol transfer protein (PITP).

Figure 3

Mitochondria-associated membranes (MAMs). The close apposition between the endoplasmic reticulum (ER) and the mitochondria allows the transport of phosphatidylserine (PS) from the ER to mitochondria, where it can be converted into phosphatidylethanolamine (PE) and transported back to the ER. The PS transport is facilitated due to a mitochondrial outer membrane nucleotide guanosine triphosphate phosphatase (GTPase), mitofusin 2 (Mfn2), which elaborates rigid domains enriched in PS, hence, facilitating PS transport through oxysterol binding protein-like 5/8 (ORP5/8). On the other hand, protein UPS1 mitochondrial (Ups1) transfers phosphatidic acid (PA) from the outer to the inner mitochondrial membrane. Abbreviations: PSS1, phosphatidylserine synthase 1; PSS2, phosphatidylserine synthase 2; PEMT, phosphatidylethanolamine N-methyltransferase; PISD, phosphatidylserine decarboxylase proenzyme; PC, phosphatidylcholine.

Figure 4

Membrane contact site between the ER and the peroxisome. Acyl-CoA binding domain-containing 5 ACBD5, a protein anchored to peroxisome membrane through its transmembrane domain (TM), interacts with vesicle-associated membrane protein-associated protein (VAP), an endoplasmic reticulum (ER) membrane protein, via its two phenylalanines (FF) in an acidic tract (FFAT)- like motif. The Acyl-CoA domain of ACBD5 transports long-chain fatty acyl-CoAs from the ER to the peroxisome.

Figure 5

Cholesterol and phosphatidylinositol 4-phosphate (PI4P) are transported between the endoplasmic reticulum (ER) and the Golgi apparatus. To maintain PI4P levels associated with cholesterol transport, phosphatidylinositol (PI) is transferred through phosphatidylinositol transport protein β (PITPβ), while the OxySterol Binding Protein (OSBP)-Related Domain (ORD motif) of Oxysterol Binding Protein (OSBP) transports cholesterol from the ER to the Golgi membrane and reciprocal transport of PI4P from Golgi membrane to the ER. Association of these two membrane structures is achieved by the interaction of the two phenylalanines (FF) in an acidic tract (FFAT)-like motif of OSBP with vesicle-associated membrane protein-associated protein (VAP) in the ER, and pleckstrin homology domain (PH domain) from OSBP, which binds to PI4P at the Golgi.

Figure 6

Graphical scheme of phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) synthesis in Mitochondria-Associated Membranes (MAMs) in healthy (left) and pathological (right) liver conditions. Phosphatidylcholine (PC) in the ER is transformed to phosphatidylserine (PS) (catalyzed by the phosphatidylserine synthase 1 (PSS1)), which is transported to mitochondria by Mitofusin 2 (Mfn2). Here, it is converted to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase proenzyme (PISD), a protein located in the mitochondrial membrane. PE is then transferred to ER, where is converted to PC or PS, depending on the enzyme implicated, phosphatidylethanolamine N-methyltransferase (PEMT), or phosphatidylserine synthase 2 (PSS2), respectively.