MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca2+ and Mn2+

Mechanisms by which heavy metals contribute to cellular toxicity are not well understood. Here, we report that cellular manganese toxicity is due in part to manganese transport into mitochondria via the calcium uniporter. Genetic loss of the uniporter's pore-forming subunit in human cells and in worms confers partial resistance against manganese toxicity, while loss of its regulatory subunit, MICU1, sensitizes human cells to manganese toxicity. MICU1 provides an additional checkpoint to discriminate between Ca²⁺ and Mn²⁺, enabling the uniporter to evolve high conductance while maintaining selectivity. Our work has implications for understanding mechanisms of manganese toxicity in neurodegenerative diseases such as Parkinson's disease.