MICU1 Confers Protection from MCU-Dependent Manganese Toxicity

Abstract

Summary: The mitochondrial calcium uniporter is a highly selective ion channel composed of species- and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co-expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure. : Wettmarshausen et al. develop a synthetic biology approach for in vivo dissection of functional interconnections between components of the mitochondrial calcium uniporter channel. They demonstrate an essential role of MICU1 in regulating MCU ion selectivity, finding that MICU1 prevents MCU-mediated Mn2+ overload and protects from Mn2+-induced cell death. Keywords: mitochondria, calcium, MCU, MICU1, yeast, manganese, signaling