Dimerization of MICU Proteins Controls Ca²⁺ Influx through the Mitochondrial Ca²⁺ Uniporter.

The mitochondrial Ca²⁺ uniporter complex (MCUC) is responsible for Ca²⁺ influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca²⁺ influx activity is controlled by regulatory subunits, including mitochondrial Ca²⁺ uptake 1 (MICU1) and its paralogs (MICU2 and MICU3). However, the underlying mechanism remains unclear. Here, we determined multiple crystal structures of MICU2 and MICU3 from Homo sapiens. Our data demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform the opposing roles in mitochondrial Ca²⁺ uptake at low cytosolic Ca²⁺ levels. In contrast, at high cytosolic Ca²⁺ levels, all MICU proteins undergo dimer rearrangement induced by Ca²⁺ binding, which releases the suppression of the MCUC pore-forming subunit and promotes the influx of large amounts of Ca²⁺. Altogether, our results elucidate the delicate mechanism of mitochondrial Ca²⁺ uptake regulation by MICU proteins.

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