Molecular mechanisms of SLC30A10-mediated manganese transport

Manganese ion (Mn²⁺) is crucial for various physiological processes, yet excessive levels disrupt cellular homeostasis and impair the function of multiple organelles. The transporter SLC30A10 plays a pivotal role in Mn²⁺ homeostasis by exporting Mn²⁺ from cells, preventing toxic effects. Mutations in the SLC30A10 gene result in Mn²⁺ accumulation and lead to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Despite its physiological significance, the structural basis underlying Mn²⁺ binding and the detailed transport mechanisms of SLC30A10 remain unknown. Here, we present diverse conformations of high-resolution cryo-electron microscopy (cryo-EM) structures that reveal a Mn²⁺-binding site in SLC30A10, setting it apart from other SLC30 family transporters. Furthermore, we show that the HMNDYT1-associated D40A mutation interrupts Mn²⁺ binding and transport, identifying D40 as a potential therapeutic target. These findings provide structural insights into Mn²⁺ transport mechanisms mediated by SLC30A10, advancing our understanding of Mn²⁺ binding and potential targets for future therapeutic exploration. Manganese is essential but toxic in excess. Here, the authors report cryo-EM structures of the Mn²⁺ transporter SLC30A10, define its Mn²⁺-binding site, and show how a disease-linked mutation impairs transport, mitochondria and cell viability, advancing understanding of Mn²⁺ homeostasis.