Cell membranes sustain phospholipid imbalance via cholesterol asymmetry, 2025, Doktorova et al.

Cell membranes sustain phospholipid imbalance via cholesterol asymmetry
Milka Doktorova; Jessica L. Symons; Xiaoxuan Zhang; Hong-Yin Wang; Jan Schlegel; Joseph H. Lorent; Frederick A. Heberle; Erdinc Sezgin; Edward Lyman; Kandice R. Levental; Ilya Levental

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.

HIGHLIGHTS
• The two leaflets of mammalian plasma membranes can differ in their lipid abundances

• Phospholipid abundance asymmetry can be stabilized by high cholesterol levels

• Phospholipid and cholesterol asymmetries produce unique membrane properties

• Cellular cholesterol homeostasis is regulated by phospholipid asymmetries

Link | PDF (Cell)