Organelle Localization and Trafficking of Ether Lipids: Current Evidence and Open Questions

Ether glycerophospholipids are abundant and functionally versatile membrane lipids whose defining sn-1 ether (plasmanyl), or vinyl ether (plasmenyl, plasmalogen) linkage, and polyunsaturated sn-2 chains provide membranes with unique biophysical and signaling properties. Biogenesis is partitioned between two organelles: peroxisomes establish the sn-1 ether linkage and deliver 1-O-alkyl intermediates to the endoplasmic reticulum, where headgroup addition and remodeling occur. Introduction of the vinyl ether double bond by plasmanylethanolamine desaturase then yields plasmalogens. Emerging evidence indicates that ether lipids are unevenly distributed across cellular membranes, reflecting both local metabolic control and selective trafficking. Biosynthetic intermediates are delivered from peroxisomes to the endoplasmic reticulum via ACBD4/5-VAPA/B membrane contact sites, which also couple ether lipid-flux to cholesterol homeostasis. At the plasma membrane, ATP8B2 flippase enforces inner leaflet enrichment of plasmalogens, linking their molecular shape to membrane curvature, raft organization, and signaling. Beyond these core sites, additional pools of ether lipids are detected in the Golgi, mitochondria, endolysosomal system, lipid droplets, and the nucleus, where they are proposed to support membrane organization, and trafficking, yet their organelle-specific functions and transport mechanisms remain poorly defined. In this review we summarize the current knowledge about cellular and subcellular distribution of ether lipids, their biosynthesis, remodeling, degradation, and intracellular trafficking. We also highlight recent methodological advances enabling organelle-resolved lipidomics and live-cell tracking of ether lipids and outline open questions regarding contact-site identity and regulation, transport specificity between plasmanyl and plasmenyl species, and pathophysiological mislocalization mechanisms.