SLC39A14 is Required for Iron Loading of the Anterior Pituitary of Mice with Genetic Iron Overload

Patients with iron overload disorders frequently accumulate iron in the pituitary and adrenal glands, leading to endocrine dysfunction. Although this iron loading is well documented, the specific molecular mechanisms of iron accumulation are not well understood. Under normal conditions, most tissues, including pituitary and adrenal gland, acquire iron from circulating transferrin. In iron overload, however, transferrin levels become saturated with iron, resulting in plasma non-transferrin-bound iron (NTBI), which becomes a significant contributor to tissue iron accumulation. Previous studies have shown that the metal-ion transport protein SLC39A14 mediates NTBI uptake in the liver and pancreas. To investigate if SLC39A14 plays a similar role in the pituitary and adrenal glands, we utilized Slc39a14 knockout (Slc39a14^-/-) mice and crossed them with hemojuvelin knockout (Hjv^-/-) mice, a model of genetic iron overload. Using Perls' staining, we found that loss of SLC39A14 in Hjv^-/-;Slc39a14^-/- mice prevented iron accumulation in the anterior pituitary, and decreased iron concentrations in pooled pituitary glands by 40% relative to Hjv^-/- mice. In contrast, iron accumulation in the posterior pituitary and adrenal gland was unaffected by the absence of SLC39A14, indicating that alternative, tissue-specific mechanisms of iron accumulation exist. We additionally observed that SLC39A14 deficiency led to elevated pituitary manganese levels, consistent with human studies. This study is the first to demonstrate that SLC39A14 is essential for iron loading in the anterior pituitary, providing new insights into the molecular pathways of metal accumulation in endocrine glands. These findings could inform the development of targeted therapies for iron overload-related endocrine complications.