Lipid Metabolism at Membrane Contacts: Dynamics and Functions Beyond Lipid Homeostasis

Abstract

Membrane contact sites (MCSs), regions where the membranes of two organelles are closely apposed, play critical roles in inter-organelle communication, such as lipid trafficking, intracellular signaling, and organelle biogenesis and division. First identified as "fraction X" in the early 90s, MCSs are now widely recognized to facilitate local lipid synthesis and inter-organelle lipid transfer, which are important for maintaining cellular lipid homeostasis. In this review, we discuss lipid metabolism and related cellular and physiological functions in MCSs. We start with the characteristics of lipid synthesis and breakdown at MCSs. Then we focus on proteins involved in lipid synthesis and turnover at these sites. Lastly, we summarize the cellular function of lipid metabolism at MCSs beyond mere lipid homeostasis, including the physiological meaning and relevance of MCSs regarding systemic lipid metabolism. This article is part of an article collection entitled: Coupling and Uncoupling: Dynamic Control of Membrane Contacts.

Keywords: lipid biosynthesis; lipid composition; lipid degradation; lipid functions; membrane contact site.

FIGURE 1

Lipid synthesis and breakdown at MCSs in mammalian cells. (A) Schematic illustration of mammalian MCSs. The contact sites discussed in the text are boxed. (B) Lipid metabolism at the ER-mitochondrion contacts, highlighting the linked synthesis of PC, PE, and PS; the detergent-resistant membrane (DRM) (domain enriched in ceramide, cholesterol, and associated proteins; and the biosynthesis of GPI using ER-derived PI and mitochondrion-derived PE. (C) Lipid metabolism at the ER-PM contacts, showing the Sac1-mediated conversion of phosphatidylinositol 4-phosphate (PI4P) to phosphatidylinositol (4,5)-bisphosphate (PIP2) in trans and in cis, and TMEM24-mediated PI transport. (D) Pex5 and ATGL interaction at peroxisome-LD contacts, and TOMM20 and ACBD2/EI2 interaction at mitochondrion-peroxisome contacts. (E) MIGA2-mediated LD-mitochondrion association to supply TAG from mitochondrially derived citrate. (F) The activation of mTORC1 by cholesterol delivered from the ER to the lysosome surface by OSBP, and the transport of cholesterol out of the lysosome lumen by NPC1. CPT, CDP-choline-1,2-diacylglycerol choline phosphotransferase (CPT); EPT, CDP-ethanolamine:1,2-diacylglycerol ethanolamine phosphotransferase; PSS1/2, phosphatidylserine synthase; PEMT, phosphatidylethanolamine methyltransferase; GPAT1, glycerophosphate acyltransferases; SIG-1R, Sigma 1R; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; G3P, glycerol-3-phosphatase; LPA, lysophosphatidic acid; GM1, GM1-ganglioside; GPI, glycosylphosphatidylinositol; TMEM24, transmembrane protein 24; PEX5, peroxisomal biogenesis factor 5; ATGL, triglyceride lipase; TOMM20, Translocase of outer mitochondrial membrane 20; ACBD2/EI2, acyl-coenzyme A-binding domain; ACLY, ATP citrate lyase; FASN, fatty acid synthase; NPC1, Niemann-Pick disease, type C1; OSBP, oxysterol-binding protein 1.)

FIGURE 2

Lipid synthesis and breakdown at MCSs in yeast. (A) Schematic illustration of yeast MCSs. The contact sites discussed in the text are boxed. (B) The mitochondrial and ER fractions of the PS decarboxylase Psd1, PI synthesis from CDP-DAG at MAMs, and PS transporter:ERMES complex. (C) The assembly of ER-Golgi contacts composed of the PS decarboxylase Psd2, Sfh4, the PI4P kinase Stt4, the tether Scs2 that binds Stt4, and Pbi1. (D) PI4P turnover at the ER-PM contact, and PC biosynthesis from PE. (E) LD-associated Pah1 at the nuclear vacuole junction. (F) Local phospholipid synthesis supports phagophore membrane expansion from the ER. (G) Concentration of the positive regulator of Torc1 (Ego complex) into sterol-enriched domains at ER-vacuole contacts. PME, phosphatidylmonomethylethanolamine; PDE, phosphatidyldimethylethanolamine.