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Doktorova M, Symons JL, Zhang X, Wang HY, Schlegel J, Lorent JH, Heberle FA, Sezgin E, Lyman E, Levental KR, Levental I
Cell - (-) - [2025-03-26; online 2025-03-26]
Membranes are molecular interfaces that compartmentalize cells to control the flow of nutrients and information. These functions are facilitated by diverse collections of lipids, nearly all of which are distributed asymmetrically between the two bilayer leaflets. Most models of biomembrane structure and function include the implicit assumption that these leaflets have similar abundances of phospholipids. Here, we show that this assumption is generally invalid and investigate the consequences of lipid abundance imbalances in mammalian plasma membranes (PMs). Using lipidomics, we report that cytoplasmic leaflets of human erythrocyte membranes have >50% overabundance of phospholipids compared with exoplasmic leaflets. This imbalance is enabled by an asymmetric interleaflet distribution of cholesterol, which regulates cellular cholesterol homeostasis. These features produce unique functional characteristics, including low PM permeability and resting tension in the cytoplasmic leaflet that regulates protein localization.
Integrated Microscopy Technologies Stockholm [Service]
PubMed 40179882
DOI 10.1016/j.cell.2025.02.034
Crossref 10.1016/j.cell.2025.02.034
pii: S0092-8674(25)00270-3