The Journal of nutrition · 2026
The Ins and Outs of Manganese: ZIP14 Facilitates Manganese Efflux from the Mouse Brain.
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Zou Jiaqi, Thorn Trista L, Wang Ziyang, Wang Yuhan, Aydemir Tolunay Beker
Аннотация
BACKGROUND: Manganese (Mn) is essential for brain function, but excess accumulation causes neurotoxicity. Mechanisms regulating Mn transport across the blood-brain barrier (BBB) remain incompletely defined. ZIP14 (SLC39A14) is implicated in systemic Mn homeostasis, but its endothelial role at the BBB is unclear.
OBJECTIVES: To define the role of endothelial ZIP14 in Mn transport at the BBB and its contribution to brain and systemic Mn homeostasis.
METHODS: Endothelial-specific Zip14 knockout (EKO) mice (C57BL/6, both sexes) and littermate controls were studied. Mn transport was assessed using nasal and subcutaneous 54Mn delivery. ZIP14 localization was examined by expansion microscopy and immunofluorescence. Directional transport was evaluated in primary mouse brain endothelial cells and ZIP14-overexpressing hCMEC/D3 cells using Transwell assays. Data were analyzed by t-test or analysis of variance (P < 0.05).
RESULTS: ZIP14 localized to brain endothelial cells and colocalized with PECAM1 (r ≈ 0.70-0.77). Mn exposure increased ZIP14 expression and basolateral localization. EKO mice showed elevated blood Mn and increased brain Mn accumulation (P < 0.01). After nasal 54Mn delivery, EKO mice exhibited greater brain Mn retention at 1 h (P < 0.05), indicating impaired efflux, whereas subcutaneous delivery did not alter uptake. In vitro, ZIP14 mediated basolateral-to-apical Mn transport (P < 0.01).
CONCLUSIONS: In mice and endothelial cells, ZIP14 mediates basolateral-to-apical Mn transport at the BBB, supporting brain-to-blood Mn movement. Endothelial Zip14 deletion disrupts Mn homeostasis, increasing circulating and brain Mn levels.
OBJECTIVES: To define the role of endothelial ZIP14 in Mn transport at the BBB and its contribution to brain and systemic Mn homeostasis.
METHODS: Endothelial-specific Zip14 knockout (EKO) mice (C57BL/6, both sexes) and littermate controls were studied. Mn transport was assessed using nasal and subcutaneous 54Mn delivery. ZIP14 localization was examined by expansion microscopy and immunofluorescence. Directional transport was evaluated in primary mouse brain endothelial cells and ZIP14-overexpressing hCMEC/D3 cells using Transwell assays. Data were analyzed by t-test or analysis of variance (P < 0.05).
RESULTS: ZIP14 localized to brain endothelial cells and colocalized with PECAM1 (r ≈ 0.70-0.77). Mn exposure increased ZIP14 expression and basolateral localization. EKO mice showed elevated blood Mn and increased brain Mn accumulation (P < 0.01). After nasal 54Mn delivery, EKO mice exhibited greater brain Mn retention at 1 h (P < 0.05), indicating impaired efflux, whereas subcutaneous delivery did not alter uptake. In vitro, ZIP14 mediated basolateral-to-apical Mn transport (P < 0.01).
CONCLUSIONS: In mice and endothelial cells, ZIP14 mediates basolateral-to-apical Mn transport at the BBB, supporting brain-to-blood Mn movement. Endothelial Zip14 deletion disrupts Mn homeostasis, increasing circulating and brain Mn levels.