The structure of the MICU1-MICU2 complex unveils the regulation of the mitochondrial calcium uniporter.

The MICU1-MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU1-MICU2 heterodimer, in which Ca²⁺ -free and Ca²⁺ -bound EF-hands are observed in both proteins, revealing both electrostatic and hydrophobic interfaces. Furthermore, we show that MICU1 interacts with EMRE, another regulator of MCU, through a Ca²⁺ -dependent alkaline groove. Ca²⁺ binding strengthens the MICU1-EMRE interaction, which in turn facilitates Ca²⁺ uptake. Conversely, the MICU1-MCU interaction is favored in the absence of Ca²⁺ , thus inhibiting the channel activity. This Ca²⁺ -dependent switch illuminates how calcium signals are transmitted from regulatory subunits to the calcium channel and the transition between gatekeeping and activation channel functions. Furthermore, competition with an EMRE peptide alters the uniporter threshold in resting conditions and elevates Ca²⁺ accumulation in stimulated mitochondria, confirming the gatekeeper role of the MICU1-MICU2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake. © 2020 The Authors.

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