| Calcium is a main signalling effector in eukaryotic cells. Therefore, its cellular concentration is tightly regulated through processes of calcium increase and decrease[1]. Among decrease processes, mitochondria are organelles capable of buffering high concentrations of calcium, and by doing so, they become central on cellular signalling and survival[2]. In humans, mitochondrial calcium uptake is mediated by a protein called MCU.[3]
Function
MCU is a highly selective uniporter that allows calcium entry into the mitochondrial matrix[4]. In metazoa, it belongs to a protein complex entitled Mitochondrial Calcium Uniporter Complex (MCUC) along with EMRE, MICU1 and MICU2, which are respectively proposed as a regulator and gatekeepers of the complex[5].
Structure
Being assembled as a tetramer, MCU monomers posses 351 amino acid residues. Each subunit can be divided into four structural domains, them being N-terminal domain (NTD), linker helix domain (LHD), coiled-coil domain (CCD), and transmembrane domain (TMD). CCD and TMD are the pore-forming subunits, while LHD links this regions to NTD. Recently, regulation of the complex and dimerization of two tetrameres were reported as functions of NTD[6].
To guarantee selectivity, 260WDIMEP265, a highly conserved sequence among protein homologues, from each monomer form two filters. The first one, dependent of D261 residues has a radius of affinity for hydrated calcium. The narrower one, is stabilized by E264 and its selective for calcium radius. Finally, there’s a second constriction point at the end of the pore, formed by residues E288 and V290 of each monomer, that are involved in a juxtamembrane loop (JML)[7].
This image is from the article "Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter" by Youxing Jiang[8]
Disease
While having a crucial role in calcium homeostasis, mitochondrial calcium uptake was already reported as protective to neuron excitotoxicity[9] and liver ischemia-reperfusion damage[10]. Therefore, mutations and dysfunction of MCU could aggravate these kinds of insult. Also, MCU could be protective to skeletal muscle age related atrophy, as suggested by it’s increase expression upon exercise stimuli[11].
- ↑ Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003 Jul;4(7):517-29. PMID:12838335 doi:10.1038/nrm1155
- ↑ Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012 Sep;13(9):566-78. doi: 10.1038/nrm3412. Epub 2012 Aug, 1. PMID:22850819 doi:https://dx.doi.org/10.1038/nrm3412
- ↑ Chaudhuri D, Sancak Y, Mootha VK, Clapham DE. MCU encodes the pore conducting mitochondrial calcium currents. Elife. 2013 Jun 4;2:e00704. doi: 10.7554/eLife.00704. PMID:23755363 doi:https://dx.doi.org/10.7554/eLife.00704
- ↑ Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira II, Allen M, Springer DA, Aponte AM, Gucek M, Balaban RS, Murphy E, Finkel T. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol. 2013 Dec;15(12):1464-72. doi: 10.1038/ncb2868. Epub 2013 Nov 10. PMID:24212091 doi:https://dx.doi.org/10.1038/ncb2868
- ↑ Finkel T, Menazza S, Holmstrom KM, Parks RJ, Liu J, Sun J, Liu J, Pan X, Murphy E. The ins and outs of mitochondrial calcium. Circ Res. 2015 May 22;116(11):1810-9. doi: 10.1161/CIRCRESAHA.116.305484. PMID:25999421 doi:https://dx.doi.org/10.1161/CIRCRESAHA.116.305484
- ↑ Lee SK, Shanmughapriya S, Mok MC, Dong Z, Tomar D, Carvalho E, Rajan S, Junop MS, Madesh M, Stathopulos PB. Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations. Cell Chem Biol. 2016 Aug 24. pii: S2451-9456(16)30242-2. doi:, 10.1016/j.chembiol.2016.07.012. PMID:27569754 doi:https://dx.doi.org/10.1016/j.chembiol.2016.07.012
- ↑ Wang Y, Nguyen NX, She J, Zeng W, Yang Y, Bai XC, Jiang Y. Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter. Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub, 2019 May 9. PMID:31080062 doi:https://dx.doi.org/10.1016/j.cell.2019.03.050
- ↑ Wang Y, Nguyen NX, She J, Zeng W, Yang Y, Bai XC, Jiang Y. Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter. Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub, 2019 May 9. PMID:31080062 doi:https://dx.doi.org/10.1016/j.cell.2019.03.050
- ↑ Amigo I, Menezes-Filho SL, Luevano-Martinez LA, Chausse B, Kowaltowski AJ. Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity. Aging Cell. 2017 Feb;16(1):73-81. doi: 10.1111/acel.12527. Epub 2016 Sep 13. PMID:27619151 doi:https://dx.doi.org/10.1111/acel.12527
- ↑ Menezes-Filho SL, Amigo I, Prado FM, Ferreira NC, Koike MK, Pinto IFD, Miyamoto S, Montero EFS, Medeiros MHG, Kowaltowski AJ. Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca(2+)-induced mitochondrial permeability transition. Free Radic Biol Med. 2017 Sep;110:219-227. doi:, 10.1016/j.freeradbiomed.2017.06.013. Epub 2017 Jun 19. PMID:28642067 doi:https://dx.doi.org/10.1016/j.freeradbiomed.2017.06.013
- ↑ Zampieri S, Mammucari C, Romanello V, Barberi L, Pietrangelo L, Fusella A, Mosole S, Gherardi G, Hofer C, Lofler S, Sarabon N, Cvecka J, Krenn M, Carraro U, Kern H, Protasi F, Musaro A, Sandri M, Rizzuto R. Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics. Physiol Rep. 2016 Dec;4(24). pii: 4/24/e13005. doi: 10.14814/phy2.13005. PMID:28039397 doi:https://dx.doi.org/10.14814/phy2.13005
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