MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake
Top Cited Papers
Open Access
- 8 August 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 467 (7313), 291-296
- https://doi.org/10.1038/nature09358
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.Keywords
This publication has 90 references indexed in Scilit:
- AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and ActivityCancer Cell, 2011
- Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and StressMolecular Cell, 2010
- Integrative Genomic Profiling of Human Prostate CancerCancer Cell, 2010
- Protein Kinase B (PKB/Akt), a Key Mediator of the PI3K Signaling PathwayCurrent topics in microbiology and immunology, 2010
- The role of Ca2+ signaling in the coordination of mitochondrial ATP production with cardiac workBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2009
- A Mitochondrial Protein Compendium Elucidates Complex I Disease BiologyCell, 2008
- High- and low-calcium-dependent mechanisms of mitochondrial calcium signallingCell Calcium, 2008
- Integration of Phosphoinositide- and Calmodulin-Mediated Regulation of TRPC6Molecular Cell, 2007
- A negative feedback signaling network underlies oncogene-induced senescenceCancer Cell, 2006
- Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosisCell Calcium, 2006