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MICU1 motifs define mitochondrial calcium uniporter binding and activity.

Hoffman N.E., Chandramoorthy H.C., Shamugapriya S., Zhang X., Rajan S., Mallilankaraman K., Gandhirajan R.K., Vagnozzi R.J., Ferrer L.M., Sreekrishnanilayam K., Natarajaseenivasan K., Vallem S., Force T., Choi E.T., Cheung J.Y., Madesh M.

Resting mitochondrial matrix Ca(2+) is maintained through a mitochondrial calcium uptake 1 (MICU1)-established threshold inhibition of mitochondrial calcium uniporter (MCU) activity. It is not known how MICU1 interacts with MCU to establish this Ca(2+) threshold for mitochondrial Ca(2+) uptake and MCU activity. Here, we show that MICU1 localizes to the mitochondrial matrix side of the inner mitochondrial membrane and MICU1/MCU binding is determined by a MICU1 N-terminal polybasic domain and two interacting coiled-coil domains of MCU. Further investigation reveals that MICU1 forms homo-oligomers, and this oligomerization is independent of the polybasic region. However, the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca(2+) current (IMCU). Moreover, MICU1 EF hands regulate MCU channel activity, but do not determine MCU binding. Loss of MICU1 promotes MCU activation leading to oxidative burden and a halt to cell migration. These studies establish a molecular mechanism for MICU1 control of MCU-mediated mitochondrial Ca(2+) accumulation, and dysregulation of this mechanism probably enhances vascular dysfunction.

Cell Rep. 5:1576-1588(2013) [PubMed] [Europe PMC]

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