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 and MICU2 are associated with the mitochondrial inner membrane, and each protein has two canonical EF hands that are essential for 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)
This family belongs to the Calmodulin/Calcineurin/KChIP (CaCa) Superfamily.
References:
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.
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.
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.
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.
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.
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.
Yuan, Y., C. Cao, M. Wen, M. Li, Y. Dong, L. Wu, J. Wu, T. Cui, D. Li, J.J. Chou, and B. OuYang. (2020). Structural Characterization of the N-Terminal Domain of the Mitochondrial Calcium Uniporter. ACS Omega 5: 6452-6460.
Examples:
TC#	Name	Organismal Type	Example
8.A.44.1.1	The mitochondrial EF hand Ca²⁺ uptake porter (MCU; TC# 1.A.77) regulator (MICU1; 476 aas) (also called Ca²⁺-binding atopy-related autoantigen CALC, or AraCALC) (Perocchi et al., 2010). It is homologous to the bifunctional glutamine amidotransferase/anthranylate phosphoribosyl transferase (PRK14607). It contributes to metabolism-insulin secretion coupling in clonal pancreatic beta-cells (Alam et al. 2012). MCU forms a complex with MICU1, MICU2 and EMRE in animals (Yuan et al. 2020). Human duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition (Dubinin et al. 2020). Cardiac mitochondria exhibit higher calcium retention capacity and higher rates of calcium uptake during sleep periods. This is associated with higher expression of clock gene Bmal1, lower expression of per2, greater expression of MICU1 gene (mitochondrial calcium uptake 1), and lower expression of the mitochondrial transition pore regulator gene cyclophilin D. Protein levels of mitochondrial calcium uniporter (MCU), MICU2, and sodium/calcium exchanger (NCLX) were also higher at sleep onset relative to wake periods. While complex I and II-dependent oxygen utilization and the transmembrane potential of cardiac mitochondria were lower during sleep, ROS production was increased, presumably due to mitochondrial calcium sequestration. Thus, retaining mitochondrial calcium in the heart during sleep dissipates the membrane potential, slows respiratory activities, and increases ROS levels, which may contribute to increased vulnerability to cardiac stress during the sleep-wake transition. This pronounced daily oscillations in mitochondrial functions pertaining to stress vulnerability may at least in part explain diurnal prevalence of cardiac pathologies.	Animals	*MICU1 of Homo sapiens* (Q9BPX6)**

8.A.44.1.2	The EF-hand-containing calcium-binding protein of the calcium uniporter, MICU2 or EFHA1 of 434 aas. Together with MICU1 (TC# 8.A.44.1.1) and EMRE, it forms a complex with and regulates Ca²⁺ uniport activity in animals (Yuan et al. 2020).	Animals	MICU2 of Homo sapiens

8.A.44.1.3	MICU1 homologue (461 aas)	Slime molds	*MICU homologue of Dictyostelium discoideum* (Q54JS1)**

8.A.44.1.4	MICU1 Homologue (373 aas)	Plants	*MICU1 of Chlorella variabilis* (E1ZEL6)**

8.A.44.1.5	Homologue of MICU1 (448 aas)	Euglenozoa	*MICU1 homologue of Leishmania mexicana* (E9AL21)**

8.A.44.1.6	MICU1 homologue (451 aas)	Algae	*MICU homologue of Chlamydomonas reinhardtii* (A8JGI1)**