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8.A.44 The Mitochondrial EF Hand Ca2+ Uniporter Regulator (MICU) Family

Mitochondrial calcium uptake plays a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients, and regulating cell death. CBARA1 has incorectly been thought to be the uniporter (Perocchi et al. 2010). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential, but abolishes mitochondrial calcium entry 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, suggesting a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high capacity mitochondrial calcium uptake (Perocchi et al., 2010). It is linked to the uniporter, MUC (TC# 1.A.77) via a 10kD 1 TMS protein called EMRE (TC# 8.A.45) in a large complex of about 480,000 Daltons (Sancak et al. 2013).

MICU homologues show limited sequence similarities to bifunctional glutamine amidotransferase/anthranilate phosphoribosyl transferase. Homologues are found in a wide range of eukaryotes. These proteins probably have 1 targetting TMSs that may be cleaved off after import into mitochondria. These proteins are homologous throughout much of their lengths to the N-terminal 300aas of EF-hand domain-containing proteins such as Arulan (2.A.29.14.1). MICU is a regulator of MCU (1.A.77) (Baughman et al., 2011), a conclusion that has been substantiated in two studies published in 2012 (Mallilankaraman et al. 2012a; Mallilankaraman et al. 2012b).  EMRE interacts with MCU and MICU via its transmembrane helices.  It maintains tight MICU regulation of the MCU pore, a role that involves EMRE binding to MICU1 using its conserved C-terminal polyaspartate tail. EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular Ca2+ landscape (Tsai et al. 2016).

The generalized reaction regulated by MICU1 and MICU2 in mammals is:

Ca2+(cytoplasm) → Ca2+(mitochondrial matrix)

References associated with 8.A.44 family:

Alam, M.R., L.N. Groschner, W. Parichatikanond, L. Kuo, A.I. Bondarenko, R. Rost, M. Waldeck-Weiermair, R. Malli, and W.F. Graier. (2012). Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic β-cells. J. Biol. Chem. 287: 34445-34454. 22904319
Baughman, J.M., F. Perocchi, H.S. Girgis, M. Plovanich, C.A. Belcher-Timme, Y. Sancak, X.R. Bao, L. Strittmatter, O. Goldberger, R.L. Bogorad, V. Koteliansky, and V.K. Mootha. (2011). Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476: 341-345. 21685886
Mallilankaraman, K., C. Cárdenas, P.J. Doonan, H.C. Chandramoorthy, K.M. Irrinki, T. Golenár, G. Csordás, P. Madireddi, J. Yang, M. Müller, R. Miller, J.E. Kolesar, J. Molgó, B. Kaufman, G. Hajnóczky, J.K. Foskett, and M. Madesh. (2012). MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat. Cell Biol. 14: 1336-1343. 23178883
Mallilankaraman, K., P. Doonan, C. Cárdenas, H.C. Chandramoorthy, M. Müller, R. Miller, N.E. Hoffman, R.K. Gandhirajan, J. Molgó, M.J. Birnbaum, B.S. Rothberg, D.O. Mak, J.K. Foskett, and M. Madesh. (2012). MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151: 630-644. 23101630
Perocchi, F., V.M. Gohil, H.S. Girgis, X.R. Bao, J.E. McCombs, A.E. Palmer, and V.K. Mootha. (2010). MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467: 291-296. 20693986
Sancak, Y., A.L. Markhard, T. Kitami, E. Kovács-Bogdán, K.J. Kamer, N.D. Udeshi, S.A. Carr, D. Chaudhuri, D.E. Clapham, A.A. Li, S.E. Calvo, O. Goldberger, and V.K. Mootha. (2013). EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342: 1379-1382. 24231807