MICU1 confers protection from MCU-dependent manganese toxicity

Wettmarshausen, Jennifer; Goh, Valerie; Huang, Kai-Ting; Arduino, Daniela M.; Tripathi, Utkarsh; Leimpek, Anja; Cheng, Yiming; Pittis, Alexandros, 1982-; Gabaldón Estevan, Juan Antonio, 1973-; Mokranjac, Dejana; Hajnóczky, György; Perocchi, Fabiana

doi:http://dx.doi.org/10.1016/j.celrep.2018.10.037

MICU1 confers protection from MCU-dependent manganese toxicity

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Wettmarshausen J, Goh V, Huang KT, Arduino DM, Tripathi U, Leimpek A et al. MICU1 confers protection from MCU-dependent manganese toxicity. Cell Rep. 2018;25(6):1425-35. DOI: 10.1016/j.celrep.2018.10.037

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.