Characterisation of alternative phospholipid synthesis pathways in mammalian cells

Mammalian cell membranes require a precisely balanced mix of phospholipids to maintain structure and function. This composition is regulated by enzymes that synthesize, degrade, and remodel lipids through fatty acid exchange. Classically, de novo synthesis begins with the formation of phosphatidic acid from glycerol‑3‑phosphate, followed by the addition of head groups via the CDP‑diacylglycerol or CDP‑choline pathways. Lipids are then modified in the Lands cycle, where phospholipase A2 generates lysophospholipids that are re‑esterified with polyunsaturated fatty acids. This remodeling influences membrane fluidity, curvature, permeability, and the function of membrane‑associated proteins.

We aim to investigate an alternative synthesis route for phospholipids not previously described in mammalian cells. We discovered that glycerophosphodiesters (GPD) - the deacylated backbones of phospholipids - can be directly re‑acylated by mammalian acyltransferases through acyl‑CoA‑dependent and ‑independent mechanisms. This pathway is more energy-efficient than classical de novo synthesis, requires fewer enzymatic steps, and may contribute to fatty acid remodeling. We hypothesize that GPD acylation represents a relevant source of phospholipid production, varying with cell type and metabolic state.

The goal of this project is to define the relevance of GPD‑dependent lipid synthesis in vitro and in vivo. The expected new insights into mammalian phospholipid metabolism may also reveal new therapeutic strategies for lipid‑related metabolic disorders, especially neurodegenerative diseases.