ZIP14 Deletion Disrupts Divalent Metal Homeostasis in Mouse Cerebrospinal Fluid

ZIP14 is a member of the SLC39A (ZIP) family of metal transporters, primarily facilitating the cellular influx of divalent metals including manganese (Mn), zinc (Zn), and iron (Fe). Previous studies have demonstrated that Zip14 knockout (Zip14^-/-) mice exhibit significant increases in whole blood and brain Mn levels. However, the impact of ZIP14 deletion on metal homeostasis within the cerebrospinal fluid (CSF) remained unexplored. In this study, we comprehensively assessed Mn, Zn, Fe, sodium (Na), potassium (K), and calcium (Ca) levels in whole blood, serum, and CSF of male and female Zip14^-/- mice to elucidate both systemic and central nervous system (CNS)-specific alterations in metal homeostasis. Our findings reveal that Zip14^-/- mice exhibit pronounced Mn accumulation, with CSF Mn levels increasing by approximately 15-fold in males and 46-fold in females compared to wild-type controls. Correspondingly, blood Mn levels rose 23-fold in males and 17-fold in females, while serum Mn levels increased 10-fold and 15-fold, respectively. In contrast, Zn and Fe levels in whole blood and serum remained comparable between Zip14^-/- and wild-type mice. However, significant elevations in CSF Zn were observed, with a sevenfold increase in males and a 16-fold increase in females, alongside a threefold rise in CSF Fe levels in females. The CSF to serum ratios of Zn and Fe remained below 1 but were increased in the knockout mice, suggesting the activation of alternative metal transporters in the absence of ZIP14, which may contribute to the increased Mn accumulation in the CSF as well. Importantly, Na⁺ and K⁺ levels in whole blood, serum, and CSF were unaltered in Zip14^-/- mice, indicating that ZIP14 deletion does not broadly disrupt systemic electrolyte balance or compromise blood—CSF barrier integrity. Conversely, CSF Ca²⁺ levels were significantly reduced by 33% in male and 23% in female Zip14^-/- mice, suggesting a specific effect of ZIP14 on calcium homeostasis within the CNS.