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

Abstract

Manganese (Mn) is an essential metal that induces incurable parkinsonism at elevated levels. However, unlike other essential metals, mechanisms that regulate mammalian Mn homeostasis are poorly understood, which has limited therapeutic development. Here, we discovered that the exposure of mice to a translationally relevant oral Mn regimen up-regulated expression of SLC30A10, a critical Mn efflux transporter, in the liver and intestines. Mechanistic studies in cell culture, including primary human hepatocytes, revealed that 1) elevated Mn transcriptionally up-regulated SLC30A10, 2) a hypoxia response element in the SLC30A10 promoter was necessary, 3) the transcriptional activities of hypoxia-inducible factor (HIF) 1 or HIF2 were required and sufficient for the SLC30A10 response, 4) elevated Mn activated HIF1/HIF2 by blocking the prolyl hydroxylation of HIF proteins necessary for their degradation, and 5) blocking the Mn-induced up-regulation of SLC30A10 increased intracellular Mn levels and enhanced Mn toxicity. Finally, prolyl hydroxylase inhibitors that stabilize HIF proteins and are in advanced clinical trials for other diseases reduced intracellular Mn levels and afforded cellular protection against Mn toxicity and also ameliorated the in vivo Mn-induced neuromotor deficits in mice. These findings define a fundamental homeostatic protective response to Mn toxicity—elevated Mn levels activate HIF1 and HIF2 to up-regulate SLC30A10, which in turn reduces cellular and organismal Mn levels, and further indicate that it may be possible to repurpose prolyl hydroxylase inhibitors for the management of Mn neurotoxicity.