TY - JOUR
T1 - MICU1 motifs define mitochondrial calcium uniporter binding and activity
AU - Hoffman, Nicholas E.
AU - Chandramoorthy, Harish C.
AU - Shamugapriya, Santhanam
AU - Zhang, Xueqian
AU - Rajan, Sudarsan
AU - Mallilankaraman, Karthik
AU - Gandhirajan, Rajesh Kumar
AU - Vagnozzi, Ronald J.
AU - Ferrer, Lucas M.
AU - Sreekrishnanilayam, Krishnalatha
AU - Natarajaseenivasan, Kalimuthusamy
AU - Vallem, Sandhya
AU - Force, Thomas
AU - Choi, Eric T.
AU - Cheung, Joseph Y.
AU - Madesh, Muniswamy
N1 - Funding Information:
We thank Douglas R. Green for cytochrome c -GFP plasmid construct. We thank Kevin J. Foskett, Donald L. Gill, and Walter J. Koch for comments on the manuscript. This research was funded by the National Institutes of Health (HL086699, HL109920, and 1S10RR027327-01).
PY - 2013/12/26
Y1 - 2013/12/26
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84891011448
UR - https://www.scopus.com/pages/publications/84891011448#tab=citedBy
U2 - 10.1016/j.celrep.2013.11.026
DO - 10.1016/j.celrep.2013.11.026
M3 - Article
C2 - 24332854
AN - SCOPUS:84891011448
SN - 2211-1247
VL - 5
SP - 1576
EP - 1588
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -