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      description: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. Uptake of calcium by mitochondria is crucial for many aspects of cellular function, and an imbalance can trigger cell death. Despite this, none of the proteins mediating mitochondrial uptake and buffering of calcium was known. Now one such protein — named 'mitochondrial calcium uptake 1' or MICU1 — has been identified. MICU1 is localized to the mitochondrion and is specifically required for calcium uptake. Genetic disruption of the MICU1 gene interrupts metabolic coupling between mitochondrial metabolism and calcium signalling. This work should facilitate the molecular characterization of mitochondrial calcium-uptake machinery and its role in normal physiology and diseases. The uptake of calcium by mitochondria has a central role in cell physiology, and an imbalance can trigger cell death. Now the first protein that is localized to the mitochondrion and is specifically required for calcium uptake has been identified. This protein, mitochondrial calcium uptake 1 (MICU1), represents the founding member of a set of proteins required for high-capacity calcium uptake. Its discovery should aid in the full molecular characterization of the mitochondrial calcium uptake pathways.
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