Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity

Significance Manganese is an essential metal, but elevated levels cause incurable parkinsonism. A major limitation in treating manganese-induced parkinsonism is a lack of understanding of the mechanisms that regulate levels of manganese in the body. This manuscript defines a homeostatic regulatory pathway for manganese in mammalian systems. Elevated manganese levels increase expression of SLC30A10, a protein that mediates manganese excretion, thereby reducing the body burden of manganese. Findings also define the involved mechanisms by showing that manganese enhances SLC30A10 expression by activating the hypoxia-inducible factor transcription cascade. Finally, the study reveals that hypoxia-inducible factor stabilizing drugs reduce manganese levels to protect cells and mice against manganese toxicity, providing a means to treat manganese-induced parkinsonism in humans.