McCabe Shannon M, Zhao Ningning
School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, Arizona, USA.
Cell Biochem Funct. 2025 Jun;43(6):e70086. doi: 10.1002/cbf.70086.
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.
ZIP14是金属转运蛋白SLC39A（ZIP）家族的成员，主要促进二价金属（包括锰（Mn）、锌（Zn）和铁（Fe））的细胞内流入。先前的研究表明，Zip14基因敲除（Zip14）小鼠的全血和脑锰水平显著升高。然而，ZIP14缺失对脑脊液（CSF）内金属稳态的影响仍未得到探索。在本研究中，我们全面评估了雄性和雌性Zip14小鼠全血、血清和脑脊液中的锰、锌、铁、钠（Na）、钾（K）和钙（Ca）水平，以阐明金属稳态在全身和中枢神经系统（CNS）的特异性改变。我们的研究结果表明，Zip14小鼠表现出明显的锰蓄积，与野生型对照相比，雄性小鼠脑脊液中的锰水平增加了约15倍，雌性小鼠增加了46倍。相应地，雄性小鼠的血锰水平上升了23倍，雌性小鼠上升了17倍，而血清锰水平分别增加了10倍和15倍。相比之下，Zip14小鼠和野生型小鼠全血和血清中的锌和铁水平相当。然而，观察到脑脊液中的锌显著升高，雄性小鼠增加了7倍，雌性小鼠增加了16倍，同时雌性小鼠脑脊液中的铁水平增加了3倍。脑脊液与血清中锌和铁的比值仍低于1，但在基因敲除小鼠中有所增加，这表明在没有ZIP14的情况下，替代金属转运蛋白被激活，这也可能导致脑脊液中锰蓄积增加。重要的是，Zip14小鼠全血、血清和脑脊液中的Na⁺和K⁺水平未发生改变，这表明ZIP14缺失不会广泛破坏全身电解质平衡或损害血脑屏障的完整性。相反，雄性Zip14小鼠脑脊液中的Ca²⁺水平显著降低了33%，雌性小鼠降低了23%，这表明ZIP14对中枢神经系统内的钙稳态有特定影响。
