MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake.

Nature
Authors
Keywords
Abstract

Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.

Year of Publication
2010
Journal
Nature
Volume
467
Issue
7313
Pages
291-6
Date Published
2010 Sep 16
ISSN
1476-4687
URL
DOI
10.1038/nature09358
PubMed ID
20693986
PubMed Central ID
PMC2977980
Links
Grant list
R01 GM077465-06 / GM / NIGMS NIH HHS / United States
R01 GM077465-04 / GM / NIGMS NIH HHS / United States
GM084027 / GM / NIGMS NIH HHS / United States
T32 GM008759 / GM / NIGMS NIH HHS / United States
R24 DK080261-04 / DK / NIDDK NIH HHS / United States
GM0077465 / GM / NIGMS NIH HHS / United States
R01 GM077465-05 / GM / NIGMS NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States
R01 GM084027 / GM / NIGMS NIH HHS / United States
TR2 GM08759 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 GM077465-03 / GM / NIGMS NIH HHS / United States
R01 GM077465-01A1 / GM / NIGMS NIH HHS / United States
DK080261 / DK / NIDDK NIH HHS / United States
R01 GM077465-02 / GM / NIGMS NIH HHS / United States
R01 GM077465 / GM / NIGMS NIH HHS / United States