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
  • 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.