2. Academic Validation
  3. MICU1 motifs define mitochondrial calcium uniporter binding and activity

MICU1 motifs define mitochondrial calcium uniporter binding and activity

  • Cell Rep. 2013 Dec 26;5(6):1576-1588. doi: 10.1016/j.celrep.2013.11.026.
Nicholas E Hoffman # 1 2,  Harish C Chandramoorthy # 1 2 3,  Santhanam Shamugapriya # 1 2,  Xueqian Zhang 2,  Sudarsan Rajan 1 2,  Karthik Mallilankaraman 1 2,  Rajesh Kumar Gandhirajan 1 2,  Ronald J Vagnozzi 2,  Lukas M Ferrer 4,  Krishnalatha Sreekrishnanilayam 1 2,  Kalimuthusamy Natarajaseenivasan 1 2,  Sandhya Vallem 1 2,  Thomas Force 2 5,  Eric T Choi 4 6,  Joseph Y Cheung 2 5,  Muniswamy Madesh 1 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.
  • 2 Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
  • 3 Stem Cell Unit & Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha P.O. 641, K S A.
  • 4 Department of Surgery, Temple University, Philadelphia, Pennsylvania, 19140, USA.
  • 5 Department of Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
  • 6 Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania, 19140, USA.
  • # Contributed equally.
PMID: 24332854 DOI: 10.1016/j.celrep.2013.11.026
Abstract

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.

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