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
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    • "The discovery of MICU1 in mammals was achieved by a phylo - genetic approach , making use of the conservation of mitochon - drial Ca 2+ uniport in most eukaryotes ( Perocchi et al . , 2010 ) . We performed a refined phylogenetic analysis for plants , confirming that MICU is conserved throughout the plant kingdom ( Figure 1A ; Supplemental Data Set 1 and Supplemental File 1 ) , which sug - gests an important functional role in plants ( Stael et al . , 2012 ) ."
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    ABSTRACT: Plant organelle function must constantly adjust to environmental conditions, which requires dynamic coordination. Ca2+ signaling may play a central role in this process. Free Ca2+ dynamics are tightly regulated and differ markedly between the cytosol, plastid stroma, and mitochondrial matrix. The mechanistic basis of compartment-specific Ca2+ dynamics is poorly understood. Here, we studied the function of At-MICU, an EF-hand protein of Arabidopsis thaliana with homology to constituents of the mitochondrial Ca2+ uniporter machinery in mammals. MICU binds Ca2+ and localizes to the mitochondria in Arabidopsis. In vivo imaging of roots expressing a genetically encoded Ca2+ sensor in the mitochondrial matrix revealed that lack of MICU increased resting concentrations of free Ca2+ in the matrix. Furthermore, Ca2+ elevations triggered by auxin and extracellular ATP occurred more rapidly and reached higher maximal concentrations in the mitochondria of micu mutants, whereas cytosolic Ca2+ signatures remained unchanged. These findings support the idea that a conserved uniporter system, with composition and regulation distinct from the mammalian machinery, mediates mitochondrial Ca2+ uptake in plants under in vivo conditions. They further suggest that MICU acts as a throttle that controls Ca2+ uptake by moderating influx, thereby shaping Ca2+ signatures in the matrix and preserving mitochondrial homeostasis. Our results open the door to genetic dissection of mitochondrial Ca2+ signaling in plants.
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    • "Venus and the calcium sensing linker D3, a calmodulin variant. It is targeted to mitochondria by the cytochrome c signal sequence, where 4 copies revealed the best targeting efficiency without disturbing mitochondrial morphology (Antigny et al., 2009; Palmer et al., 2006; Perocchi et al., 2010). For confocal imaging fluorescence of the Venus protein was measured, showing a basal fluorescence in the calcium unbound form and an increased fluorescence intensity upon binding of calcium ions. "
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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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