Mono- and Polyunsaturated Phosphatidic Acid Regulate Distinct Steps of Regulated Exocytosis in Neuroendocrine Cells

Specific forms of fatty acids have beneficial health effects, but their precise mechanism of action remains elusive. Among them, poly-unsaturated fatty acids have been proposed to prevent cognitive decline. Here we investigated the role of phosphatidic acid produced by phospholipase D1 in the sequential stages underlying secretory granule exocytosis in neuroendocrine chromaffin cells. Lipidomic revealed that stimulation triggers the selective production of several PA species at the plasma membrane, located preferentially in the close vicinity of docked granules near the sites of active exocytosis. Rescue experiments in chromaffin cells depleted of PLD1 activity reveal that mono-unsaturated PA restores the number of exocytotic events most likely by contributing to granule recruitment/docking while poly-unsaturated PA regulates fusion pore stability and expansion. Altogether, this work opens a novel insight into the different roles in a given cellular function that subspecies of the same phospholipid may play based on their fatty acyl chain composition.