Mechanisms of Manganese Transport by SLC30A10 in Maintaining Mitochondrial Homeostasis

Manganese (Mn) is an essential trace element required for various physiological processes, yet excessive levels induce oxidative stress and lead to severe health issues. The transporter SLC30A10 is crucial for maintaining Mn homeostasis by exporting Mn from cells to prevent toxic accumulation. Mutations in the SLC30A10 gene disrupt this function, resulting in manganese accumulation, which leads to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Here, we show that SLC30A10 mediates Mn efflux under elevated Mn conditions, alleviating oxidative stress and preserving mitochondrial integrity. High-resolution cryo-EM structures reveal a unique Mn-binding site in SLC30A10, setting it apart from other SLC30 family transporters. We further demonstrate that the HMNDYT1-linked D40A mutation disrupts the binding and transport of Mn, identifying D40 as a potential therapeutic target. These findings provide structural insights into Mn transport and potential avenues for targeting Mn toxicity.