# Critique of a Radically New Model for Plasma Membrane Bilayer Organization

## TL;DR

This paper critiques a new model of plasma membrane organization that contradicts existing scientific understanding.

## Contribution

The paper identifies flaws in a novel model of lipid distribution in cell membranes.

## Key findings

- Incomplete digestion by phospholipase A2 can be explained by product inhibition.
- Ultrastructural analysis shows most phosphatidylcholine is in the outer leaflet.
- High cholesterol concentration in the outer leaflet is not detectable by probes.

## Abstract

A novel model recently proposed by Doktorova et al. challenges current concepts for the molecular organization of the plasma membrane bilayer. It is at odds with previously published research. The model posits that there are far fewer phospholipid molecules in the outer leaflet of the bilayer than in the inner leaflet and that the resulting area deficit is filled by cholesterol. This conclusion is based on the incomplete hydrolysis of the phosphatidylcholine in intact erythrocytes by phospholipase A2, leading to the inference that the undigested fraction is endofacial. But the incomplete digestion can be explained by product inhibition. Furthermore, ultrastructural analysis has shown that almost all of the phosphatidylcholine in the erythrocyte bilayer resides in the outer leaflet. Finally, the high concentration of cholesterol predicted for the outer leaflet of resting human erythrocytes is not detectable by probes. The conflict of the new model with the literature makes it insecure.

We critique a model by Doktorova et al. (doi.org/10.1016/j.cell.2025.02.034) that challenges textbook depictions of the distribution of lipids in plasma membrane bilayers. They propose that the outer leaflet has about half as many phospholipids as the inner leaflet (left figure) and is compensated for by an excess of cholesterol (right figure).