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bioRxiv · 10.1101/371419

MICU1 modulates MCU ion selectivity and tolerance to manganese stress

Perocchi, F.·Wettmarshausen, J.·Goh, V.·Tripathi, U.·Leimpek, A.·Cheng, Y.·Pittis, A. A.·Gabaldon, T.·Mokranjac, D.
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Abstract

The mitochondrial calcium uniporter is a highly selective ion channel composed of species-and tissue-specific structural and regulatory subunits. However, the contribution of each component to uniporter-mediated activity still remains unclear. Here, we employ an evolutionary and synthetic biology approach to investigate the functional inter-dependence between the pore-forming subunit MCU and the EF-hand protein MICU1. Using phylogenetic profiling and genetic complementation analyses, we show that MCU and MICU1 constitute the minimal eukaryotic unit of the uniporter, pointing towards a strong selective pressure behind their co-occurrence. Heterologous reconstitution of MCU-mediated and MICU1-gated mitochondrial calcium entry in vivo in yeast cells demonstrates that MICU1 per se is essential to protect yeast from MCU-dependent manganese cytotoxicity. Accordingly, MICU1 deletion significantly sensitizes human HEK-293 cells to manganese-induced stress. Our study identifies a critical role of MICU1 in the regulation of MCU ion selectivity, with potential implications for patients with MICU1 deficiency.

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Perocchi, F., Wettmarshausen, J., Goh, V., Tripathi, U., Leimpek, A., Cheng, Y., Pittis, A. A., Gabaldon, T., Mokranjac, D.. 2018-07-17. MICU1 modulates MCU ion selectivity and tolerance to manganese stress. https://doi.org/10.1101/371419

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