Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

Prajapati, M.; Zhang, J. Z.; Chong, G. S.; Chiu, L.; Mercadante, C. J.; Kowalski, H. L.; Antipova, O.; Lai, B.; Ralle, M.; Jackson, B. P.; Punshon, T.; Guo, S.; Aghajan, M.; Bartnikas, T. B.

doi:10.1101/2024.07.17.603814

bioRxiv · 10.1101/2024.07.17.603814

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

Prajapati, M.·Zhang, J. Z.·Chong, G. S.·Chiu, L.·Mercadante, C. J.·Kowalski, H. L.·Antipova, O.·Lai, B.·Ralle, M.·Jackson, B. P.·Punshon, T.·Guo, S.·Aghajan, M.·Bartnikas, T. B.

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Abstract

SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

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Prajapati, M., Zhang, J. Z., Chong, G. S., Chiu, L., Mercadante, C. J., Kowalski, H. L., Antipova, O., Lai, B., Ralle, M., Jackson, B. P., Punshon, T., Guo, S., Aghajan, M., Bartnikas, T. B.. 2024-07-20. Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption. https://doi.org/10.1101/2024.07.17.603814

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