MFSD2A in focus: the molecular mechanism of omega-3 fatty acid transport

Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients required to support growth, maintenance, and function of the central nervous system (CNS). While the brain has a high demand for DHA, it cannot synthesize it de novo and thus relies on its uptake from the bloodstream. Circulating DHA is primarily obtained from dietary sources and is transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC-DHA) by the transmembrane transporter Major Facilitator Superfamily Domain containing 2A (MFSD2A), in a sodium-dependent manner. Here we provide a comprehensive analysis of recent insights gained from structural, functional and computational studies of MFSD2A. We focus on the mechanism by which this transporter mediates sodium-dependent uptake of LPC-DHA, and lysolipids more broadly, highlighting different conformational states, substrate entry and release pathways, and the ligand binding sites. This review presents a detailed overview of the molecular mechanism that enables MFSD2A to supply the brain with this essential nutrient, while simultaneously providing biophysical insights into how lysolipids are transported across biological membranes.