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LIPID TRANSPORT

Fatty acid transporter MFSD2A is a multifunctional gatekeeper in brain and placenta

Nature Structural & Molecular Biology volume 29, pages 504–506 (2022)Cite this article

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MFSD2A mediates uptake of the essential fatty acid DHA across the blood–brain barrier. Separately, via interactions with syncytin-2, MFSD2A contributes to the formation of the mother–fetus placental boundary. Cryo-EM analysis of a human MFSD2A–syncytin-2 complex provides new insights into how MFSD2A performs these dual roles.

In 2014, MFSD2A was pinpointed as the long-sought import conduit at the BBB for sodium-dependent uptake of docosahexaenoic acid (DHA), the most abundant omega-3 fatty acid in the central nervous system (CNS)3,4. Highly expressed at the luminal BBB surface, MFSD2A transports DHA not as a free fatty acid but as an esterified single-tail phospholipid, lysophosphatidylcholine-DHA (LPC-DHA)5 (Fig. 1a). Competition experiments demonstrate that MFSD2A transport specificity is not restricted to DHA, but requires that fatty acyl chains be coupled to the zwitterionic phosphocholine headgroup and have an aliphatic tail length of at least 14 carbon atoms6. MFSD2A dysfunction can result in congenital microcephaly and increased BBB permeability7,8. Two recent cryo-electron microscopy (cryo-EM) studies of MFSD2A homologs revealed the conserved architecture of the protein and were in general agreement about the probable location of LPC-headgroup-coordinating residues9,10. However, these reports proposed conflicting models for a LPC-DHA translocation mechanism, and an open question has concerned the means by which MFSD2A occludes and ‘flips’ long lipid tail groups of at least 14 carbons during transport.

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Fig. 1: Multiple barrier functions of MFSD2A in brain and placenta.
Fig. 2: Lipid transport mechanisms are coming into focus.

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Acknowledgements

Research in the lab of M.A.S. is funded by the European Research Council (ERC; consolidator grant no. 772190) and by a project grant of the Swiss National Science Foundation (310030_188817).

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  1. Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland

    Justin D. Walter, Sille Remm & Markus A. Seeger

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  1. Justin D. Walter
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  3. Markus A. Seeger
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Correspondence to Justin D. Walter or Markus A. Seeger.

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Walter, J.D., Remm, S. & Seeger, M.A. Fatty acid transporter MFSD2A is a multifunctional gatekeeper in brain and placenta. Nat Struct Mol Biol 29, 504–506 (2022). https://doi.org/10.1038/s41594-022-00788-6

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