ArticleProceedings of the National Academy of Sciences of the United States of America2023
Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Plasma lipidomic and metabolomic profiles in high-grade glioma patients before and after 72-h presurgery water-only fasting.Molecular oncology · 2025Trial
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- MFSD2A in health and disease: lysolipid transport, barrier physiology, and translational boundaries.Molecular biomedicine · 2026Review
- Cellular and signalling mechanisms that regulate the blood-brain barrier.Nature reviews. Molecular cell biology · 2026Review
- Structure and allostery in major facilitator superfamily symport mechanisms.Acta crystallographica. Section D, Structural biology · 2026Article
- Adipose Tissue-Central Nervous System Axis in Obesity: Molecular Mechanisms, Inflammation, and Nutritional and Technological Implications.Metabolites · 2026Review
- Mfsd2a is important for maintaining epidermal homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Article
- A Lipid Road to Neuroimmunology: Fatty Acids Linking Immune and Nervous Systems.Neuroimmunomodulation · 2026Review
- MFSD2A: a molecular nexus linking blood-brain barrier, lipid metabolism, and ischemia-reperfusion injury.Cellular & molecular biology letters · 2025Review
- Reviewing vascular influences on neuronal migration, cortical development, and neurodevelopmental disorders: focus on autism, ADHD and schizophrenia.Molecular psychiatry · 2025Review
- Allosteric effects of the coupling cation in melibiose transporter MelB.bioRxiv : the preprint server for biology · 2025Article
- Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.Cell metabolism · 2025Article
- MFSD2A in Focus: the Molecular Mechanism of Omega-3 Fatty Acid Transport.Physiology (Bethesda, Md.) · 2025Review
- Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.Cancer & metabolism · 2025Article
- Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Lipid profiling identifies modifiable signatures of cardiometabolic risk in children and adolescents with obesity.Nature medicine · 2025Article
- Cellular and organismal function of choline metabolism.Nature metabolism · 2025Review
- Novel approach to enhancing brain DHA uptake: the role of nannochloropsis microalgae extract.Frontiers in nutrition · 2025Article
- Interplay between the brain and adipose tissue: a metabolic conversation.EMBO reports · 2024Review
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12 authors.
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Abstract
Major Facilitator Superfamily Domain containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine (LPC) transporter expressed at the blood-brain barrier that constitutes the main pathway by which the brain obtains omega-3 fatty acids, such as docosahexanoic acid. Mfsd2a deficiency in humans results in severe microcephaly, underscoring the importance of LPC transport by Mfsd2a for brain development. Biochemical studies and recent cryo-electron microscopy (cryo-EM) structures of Mfsd2a bound to LPC suggest that Mfsd2a transports LPC via an alternating access mechanism between outward-facing and inward-facing conformational states in which the LPC inverts during transport between the outer and inner leaflet of a membrane. However, direct biochemical evidence of flippase activity by Mfsd2a has not been demonstrated and it is not understood how Mfsd2a could invert LPC between the outer and inner leaflet of the membrane in a sodium-dependent manner. Here, we established a unique in vitro assay using recombinant Mfsd2a reconstituted in liposomes that exploits the ability of Mfsd2a to transport lysophosphatidylserine (LPS) coupled with a small molecule LPS binding fluorophore that allowed for monitoring of directional flipping of the LPS headgroup from the outer to the inner liposome membrane. Using this assay, we demonstrate that Mfsd2a flips LPS from the outer to the inner leaflet of a membrane bilayer in a sodium-dependent manner. Furthermore, using cryo-EM structures as guides together with mutagenesis and a cell-based transport assay, we identify amino acid residues important for Mfsd2a activity that likely constitute substrate interaction domains. These studies provide direct biochemical evidence that Mfsd2a functions as a lysolipid flippase.
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