MICU1 Encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nature (Impact Factor: 41.46). 09/2010; 467(7313):291-6. DOI: 10.1038/nature09358
Source: PubMed


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, Oct 08, 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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    • "MCU comprises a membrane-spanning 40 kDa protein that forms a low conductance Ca2+-selective channel pore [3], [4], [5]. Important regulators of MCU activity have been discovered including MICU1 [6] and MICU2 [7], MCUR1 [8] and EMRE [9]. Ca2+ transporters that extrude Ca2+ from the matrix have also been characterised recently, including the mitochondrial Na+-Ca2+ exchanger [10] and Letm1 [11], a Ca2+-H+ exchanger. "
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    ABSTRACT: Ca2+ flux into mitochondria is an important regulator of cytoplasmic Ca2+ signals, energy production and cell death pathways. Ca2+ uptake can occur through the recently discovered mitochondrial uniporter channel (MCU) but whether the MCU is involved in shaping Ca2+ signals and downstream responses to physiological levels of receptor stimulation is unknown. Here, we show that modest stimulation of leukotriene receptors with the pro-inflammatory signal LTC4 evokes a series of cytoplasmic Ca2+ oscillations that are rapidly and faithfully propagated into mitochondrial matrix. Knockdown of MCU or mitochondrial depolarisation, to reduce the driving force for Ca2+ entry into the matrix, prevents the mitochondrial Ca2+ rise and accelerates run down of the oscillations. The loss of cytoplasmic Ca2+ oscillations appeared to be a consequence of enhanced Ca2+-dependent inactivation of InsP3 receptors, which arose from the loss of mitochondrial Ca2+ buffering. Ca2+ dependent gene expression in response to leukotriene receptor activation was suppressed following knockdown of the MCU. In addition to buffering Ca2+ release, mitochondria also sequestrated Ca2+ entry through store-operated Ca2+ channels and this too was prevented following loss of MCU. MCU is therefore an important regulator of physiological pulses of cytoplasmic Ca2+.
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    • "Next, we analyzed the single gene MICU1. We had previously used simple phylogenetic profiling with three species in combination with RNAi assays to identify MICU1 as a regulatory subunit of the mitochondrial calcium uniporter channel (Perocchi et al., 2010). The CLIME expansion, ECM+, contained eight genes with similar histories, including four genes recently shown to encode additional components of the channel (MCU, MCUb, MICU2, and MICU3; Sancak et al., 2013). "
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