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Wettmarshausen, Jennifer; Goh, Valerie; Huang, Kai-Ting; Arduino, Daniela M.; Tripathi, Utkarsh; Leimpek, Anja; Cheng, Yiming; Pittis, Alexandros A.; Gabaldon, Toni; Mokranjac, Dejana; Hajnoczky, Gyorgy; Perocchi, Fabiana (2018): MICU1 Confers Protection from MCU-Dependent Manganese Toxicity. In: Cell Reports, Vol. 25, No. 6: pp. 1425-1435
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Abstract

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.