MICU1 motifs define mitochondrial calcium uniporter binding and activity

Nicholas E. Hoffman, Harish C. Chandramoorthy, Santhanam Shamugapriya, Xueqian Zhang, Sudarsan Rajan, Karthik Mallilankaraman, Rajesh Kumar Gandhirajan, Ronald J. Vagnozzi, Lucas M. Ferrer, Krishnalatha Sreekrishnanilayam, Kalimuthusamy Natarajaseenivasan, Sandhya Vallem, Thomas Force, Eric T. Choi, Joseph Y. Cheung, Muniswamy Madesh

Research output: Contribution to journalArticle

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Abstract

Resting mitochondrial matrix Ca2+ 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 Ca2+ threshold for mitochondrial Ca2+ 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 thepolybasic region. However, the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca2+ 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 Ca2+ accumulation, and dysregulation of this mechanism probably enhances vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)1576-1588
Number of pages13
JournalCell Reports
Volume5
Issue number6
DOIs
StatePublished - Dec 26 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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. (2013). MICU1 motifs define mitochondrial calcium uniporter binding and activity. Cell Reports, 5(6), 1576-1588. https://doi.org/10.1016/j.celrep.2013.11.026