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

The mitochondrial uniporter is a Ca²⁺-activated Ca²⁺ channel complex that displays exceptionally high conductance and selectivity. Here, we report cellular metal toxicity screens highlighting the uniporter's role in Mn²⁺ toxicity. Cells lacking the pore-forming uniporter subunit, MCU, are more resistant to Mn²⁺ toxicity, while cells lacking the Ca²⁺-sensing inhibitory subunit, MICU1, are more sensitive than the wild type. Consistent with these findings, Caenorhabditis elegans lacking the uniporter's pore have increased resistance to Mn²⁺ toxicity. The chemical-genetic interaction between uniporter machinery and Mn²⁺ toxicity prompted us to hypothesize that Mn²⁺ can indeed be transported by the uniporter's pore, but this transport is prevented by MICU1. To this end, we demonstrate that, in the absence of MICU1, both Mn²⁺ and Ca²⁺ can pass through the uniporter, as evidenced by mitochondrial Mn²⁺ uptake assays, mitochondrial membrane potential measurements, and mitoplast electrophysiology. We show that Mn²⁺ does not elicit the conformational change in MICU1 that is physiologically elicited by Ca²⁺, preventing Mn²⁺ from inducing the pore opening. Our work showcases a mechanism by which a channel's auxiliary subunit can contribute to its apparent selectivity and, furthermore, may have implications for understanding how manganese contributes to neurodegenerative disease. [ABSTRACT FROM AUTHOR]