MICU1 encodes a mitochondrial EF hand protein required for Ca uptake

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nature (Impact Factor: 42.35). 09/2010; 467(7313):291-6. DOI: 10.1038/nature09358
Source: PubMed

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.

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Available from: Vishal M Gohil, Jul 28, 2015
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    • "Instead, internal free calcium is taken up by the ER and mitochondria (Eisner et al., 2013; Hajnoczky et al., 2014). Mitochondrial calcium uptake is mediated by calcium transporters (in particular by the mitochondrial calcium uniporter mCU and by uncoupling proteins, UCPs (Perocchi et al., 2010; Baughman et al., 2011; De Stefani et al., 2011; Drago et al., 2011; Waldeck-Weiermair et al., 2011; Mallilankaraman et al., 2012 "
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    • "Furthermore , as discussed in more detail below, Patron et al. [43] have recently suggested that MICU1 is a direct activator of MCU. Originally shown to be strongly associated with the inner mitochondrial membrane [33], MICU1 is predicted to have a transmembrane domain and it is relatively resistant to carbonate extraction [41], suggesting that it might be an integral membrane protein. "
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    • "Mitochondrial Ca 2+ uptake 1 ( MICU1 ) is a mitochondrial protein containing two canonical Ca 2+ - sensing EF - hands ( Perocchi et al . 2010 ) and interacts with the MCU ( Baughman et al . 2011 ; Mallilankaraman et al . 2012b ) . Si - lencing of MICU1 strikingly reduced mitochondrial Ca 2+ uptake in one study ( Perocchi et al . 2010 ) , whereas others reported a constitutively increased mitochondrial Ca 2+ con - centration under resting conditions but no effect on mitochon - drial Ca 2+ uptake by the MCU ( Mallilankaraman et al . 2012b ) . MICU1 appears to function as a gatekeeper for MCU - mediated mitochondrial Ca 2+ uptake and limits mitochondrial Ca 2+ uptake o"
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