Overlaps in mammalian iron and manganese homeostasis: recent advances

Iron and manganese are essential nutrients yet toxic in excess. Given this, levels of these metals are carefully regulated in the body by specific molecular mechanisms. In this review, we discuss recently reported overlaps in iron and manganese homeostasis in mammalian systems, with a focus on intestinal absorption and gastrointestinal excretion. We begin with the current understanding of iron and manganese homeostasis, then present causes and consequences of imbalances in levels of these metals in the body. Notably, while manganese is best known as a neurotoxicant, multiple recent studies have reported that variations in manganese levels correlate with a wide variety of parameters of health and disease. We then highlight deficiency in the manganese transport protein SLC30A10, the first reported inherited cause of manganese excess, and recent studies of SLC30A10 from our group and others that demonstrate three intriguing overlaps between iron and manganese homeostasis. First, intestinal iron transporters DMT1 and ferroportin are essential for manganese absorption and overload in SLC30A10 deficiency. Second, intestinal SLC30A10 downregulates manganese absorption when pathways of iron absorption are upregulated. Third, manganese excess promotes SLC30A10 expression by perturbing regulation of hypoxia-inducible factors, transcription factors that are essential for the cellular response to iron imbalance. We also briefly review SLC39A14 and SLC39A8 deficiency, two other inherited diseases of manganese imbalance, and the current understanding of the function of SLC39A14 and SLC39A8. We conclude with a discussion of active, unresolved questions in need of further investigation that will enhance our understanding of the interplay between iron and manganese homeostasis in mammalian systems.