MCU
entrez
90550
canonical
uniprot
Q8NE86
canonical
ensembl
ENSG00000156026
resolver
ensp
ENSP00000349680
resolver
ensp
ENSP00000362144
resolver
ensp
ENSP00000440913
resolver
genesymbol
MCU
resolver
genesymbol_syn
C10orf42
resolver
genesymbol_syn
CCDC109A
resolver
hgnc
HGNC:23526
resolver
uniprot
B2RDF3
resolver
uniprot
B3KXV7
resolver
uniprot
Q96FL3
resolver
uniprot_entry
MCU_HUMAN
resolver
uniprot_sec
B2RDF3
resolver
uniprot_sec
B3KXV7
resolver
uniprot_sec
Q96FL3
resolver
activity_regulation
ACTIVITY REGULATION: MCU channel activity is regulated by the heterodimer composed of MICU1 and either MICU2 or MICU3, which act as calcium-sensors (PubMed:24560927, PubMed:26903221, PubMed:32494073, PubMed:32762847, PubMed:37036971, PubMed:37126688). At low calcium levels, MICU1 occludes the pore of the MCU channel, preventing mitochondrial calcium uptake (PubMed:32494073, PubMed:32762847, PubMed:37036971, PubMed:37126688). At higher calcium levels, calcium-binding to MICU1 and MICU2 (or MICU3) induces a conformational change that weakens MCU-MICU1 interactions and moves the MICU1-MICU2 heterodimer away from the pore, allowing calcium permeation through the channel (PubMed:32494073, PubMed:32762847). MCU channel activity is gated by EMRE/SMDT1 via the juxtamembrane helix loop (PubMed:31080062, PubMed:33296646). Inhibited by ruthenium red or its derivative Ru360 (PubMed:23755363, PubMed:37036971, PubMed:37126688). {ECO:0000269|PubMed:23755363, ECO:0000269|PubMed:24560927, ECO:0000269|PubMed:26903221, ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073, ECO:0000269|PubMed:32762847, ECO:0000269|PubMed:33296646, ECO:0000269|PubMed:37036971, ECO:0000269|PubMed:37126688}.
uniprot
proteins
amino_acid_sequence
MAAAAGRSLLLLLSSRGGGGGGAGGCGALTAGCFPGLGVSRHRQQQHHRTVHQRIASWQNLGAVYCSTVVPSDDVTVVYQNGLPVISVRLPSRRERCQFTLKPISDSVGVFLRQLQEEDRGIDRVAIYSPDGVRVAASTGIDLLLLDDFKLVINDLTYHVRPPKRDLLSHENAATLNDVKTLVQQLYTTLCIEQHQLNKERELIERLEDLKEQLAPLEKVRIEISRKAEKRTTLVLWGGLAYMATQFGILARLTWWEYSWDIMEPVTYFITYGSAMAMYAYFVMTRQEYVYPEARDRQYLLFFHKGAKKSRFDLEKYNQLKDAIAQAEMDLKRLRDPLQVHLPLRQIGEKD
uniprot
proteins
function
FUNCTION: Channel-forming and calcium-conducting subunit of the mitochondrial inner membrane calcium uniporter complex (uniplex), which mediates calcium uptake into the mitochondrial matrix (PubMed:21685886, PubMed:21685888, PubMed:22822213, PubMed:22829870, PubMed:22904319, PubMed:23101630, PubMed:23178883, PubMed:23755363, PubMed:24332854, PubMed:24560927, PubMed:26341627, PubMed:29954988, PubMed:29995857, PubMed:30454562, PubMed:30638448, PubMed:31080062, PubMed:32494073, PubMed:32762847, PubMed:33296646, PubMed:37036971, PubMed:37126688). MCU channel activity is regulated by the calcium-sensor subunits of the uniplex MICU1 and MICU2 (or MICU3) (PubMed:24560927, PubMed:26903221, PubMed:30454562, PubMed:30638448, PubMed:32494073, PubMed:32762847, PubMed:37036971, PubMed:37126688). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates ATP production, cytoplasmic calcium signals and activation of cell death pathways (PubMed:21685886, PubMed:21685888, PubMed:22822213, PubMed:22829870, PubMed:22904319, PubMed:23101630, PubMed:23178883, PubMed:23755363, PubMed:24332854, PubMed:24560927, PubMed:26341627, PubMed:29954988, PubMed:32494073, PubMed:32762847). Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes (PubMed:22822213). While dispensable for baseline homeostatic cardiac function, acts as a key regulator of short-term mitochondrial calcium loading underlying a 'fight-or-flight' response during acute stress: acts by mediating a rapid increase of mitochondrial calcium in pacemaker cells (PubMed:25603276). Participates in mitochondrial permeability transition during ischemia-reperfusion injury (By similarity). Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults (By similarity). Regulates synaptic vesicle endocytosis kinetics in central nerve terminal (By similarity). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22829870, PubMed:22904319). Involved in antigen processing and presentation (By similarity). {ECO:0000250|UniProtKB:Q3UMR5, ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:21685888, ECO:0000269|PubMed:22822213, ECO:0000269|PubMed:22829870, ECO:0000269|PubMed:22904319, ECO:0000269|PubMed:23101630, ECO:0000269|PubMed:23178883, ECO:0000269|PubMed:23755363, ECO:0000269|PubMed:24332854, ECO:0000269|PubMed:24560927, ECO:0000269|PubMed:25603276, ECO:0000269|PubMed:26341627, ECO:0000269|PubMed:26903221, ECO:0000269|PubMed:29954988, ECO:0000269|PubMed:29995857, ECO:0000269|PubMed:30454562, ECO:0000269|PubMed:30638448, ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073, ECO:0000269|PubMed:32762847, ECO:0000269|PubMed:33296646, ECO:0000269|PubMed:37036971, ECO:0000269|PubMed:37126688}.
uniprot
proteins
mass_dalton
39867
uniprot
proteins
mutagenesis
MUTAGEN 57; /note="S->A: Decreased MCU current; when associated with A-92."; /evidence="ECO:0000269|PubMed:23051746"; MUTAGEN 66; /note="C->A: Does not affect glutathionylation in response to reactive oxygen species."; /evidence="ECO:0000269|PubMed:28262504"; MUTAGEN 92; /note="S->A: Decreased MCU current; when associated with A-57."; /evidence="ECO:0000269|PubMed:23051746"; MUTAGEN 92; /note="S->A: Impairs calcium uptake, but has no effect on oligomerization and interaction with MICU1 and MICU2."; /evidence="ECO:0000269|PubMed:26341627"; MUTAGEN 97; /note="C->A: Abolished glutathionylation in response to reactive oxygen species."; /evidence="ECO:0000269|PubMed:28262504"; MUTAGEN 123; /note="D->R: No effect on calcium uptake in presence of high concentrations of calcium. Abolished dimerization of MCU."; /evidence="ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073"; MUTAGEN 180; /note="K->A: No effect on calcium uptake, oligomerization and interaction with MICU1 and MICU2."; /evidence="ECO:0000269|PubMed:26341627"; MUTAGEN 191; /note="C->A: Does not affect glutathionylation in response to reactive oxygen species."; /evidence="ECO:0000269|PubMed:28262504"; MUTAGEN 240; /note="L->W: Abolished calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 241; /note="A->W: Abolished interaction with EMRE/SMDT1 and calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 248; /note="G->W: Abolished calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 257; /note="E->A: According to a report, inhibits calcium uptake. According to a subsequent report, does not affect greatly calcium uptake."; /evidence="ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:27135929"; MUTAGEN 257; /note="E->S: Does not affect greatly calcium uptake."; /evidence="ECO:0000269|PubMed:27135929"; MUTAGEN 259; /note="S->A: Does not inhibit calcium uptake. Strongly reduced sensitivity to ruthenium red inhibition."; /evidence="ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:23755363"; MUTAGEN 259; /note="S->R: Prevents entrance of calcium into the pore."; /evidence="ECO:0000269|PubMed:27135929, ECO:0000269|PubMed:30638448"; MUTAGEN 260; /note="W->A,F,Y: Abolished mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29954988, ECO:0000269|PubMed:29995857"; MUTAGEN 261..264; /note="DIME->AIMA: Dominant negative (DN) mutant; inhibits calcium uptake. Inhibits calcium channel activity. Expression of the dominant negative protein in mice, leads to mice that are incapable of physiological fight or flight heart rate acceleration."; /evidence="ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:21685888, ECO:0000269|PubMed:25603276"; MUTAGEN 261; /note="D->A,Q: Abolished interaction with MICU1."; /evidence="ECO:0000269|PubMed:30638448"; MUTAGEN 261; /note="D->E: Partially functional; does not completely abolish calcium channel activity. Does not affect interaction with MICU1."; /evidence="ECO:0000269|PubMed:27135929, ECO:0000269|PubMed:30638448"; MUTAGEN 262; /note="I->V,A: Does not affect mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29995857"; MUTAGEN 263; /note="M->A: Reduced but not abolished mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29995857"; MUTAGEN 264; /note="E->A: Does not affect interaction with MICU1."; /evidence="ECO:0000269|PubMed:30638448"; MUTAGEN 264; /note="E->D: Abolished mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:27135929, ECO:0000269|PubMed:29995857"; MUTAGEN 265; /note="P->A,G: Abolished mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29995857"; MUTAGEN 267; /note="T->A: Reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29954988"; MUTAGEN 268; /note="Y->A: Reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29954988"; MUTAGEN 268; /note="Y->F: Does not affect mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:29954988"; MUTAGEN 286; /note="R->Q: Abolished gating by EMRE/SMDT1, leading to reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 288; /note="E->S: Abolished gating by EMRE/SMDT1, leading to reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 289; /note="Y->F: Abolished gating by EMRE/SMDT1, leading to reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 289; /note="Y->F: Mitochondrial calcium uptake in the absence of EMRE/SMDT1."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 290; /note="V->E: Abolished gating by EMRE/SMDT1, leading to reduced mitochondrial calcium uptake."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 291; /note="Y->F,A,T,K: Does not affect gating by EMRE/SMDT1."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 294; /note="A->C,S: No effect."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 294; /note="A->F,L: Mitochondrial calcium uptake in the absence of EMRE/SMDT1."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 294; /note="A->N,K: Abolished mitochondrial calcium uptake even in the presence of EMRE/SMDT1."; /evidence="ECO:0000269|PubMed:33296646"; MUTAGEN 297; /note="R->A,L: Decreased interaction with EMRE/SMDT1, leading to reduced calcium channel import."; /evidence="ECO:0000269|PubMed:33296646
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by CaMK2 in heart leads to increased MCU current (PubMed:23051746, PubMed:25254481). The regulation of MCU by CaMK2 is however subject to discussion: another group was unable to reproduce these results (PubMed:25254480). Phosphorylated on tyrosines by PTK2B/PYK2, promoting oligomerization (PubMed:24800979). {ECO:0000269|PubMed:24800979, ECO:0000305|PubMed:23051746, ECO:0000305|PubMed:25254480, ECO:0000305|PubMed:25254481}.; PTM: Glutathionylation at Cys-97 in response to reactive oxygen species (ROS) promotes MCU higher-order assembly, leading to constitutive activation of the MCU channel and mitochondrial calcium overload. {ECO:0000269|PubMed:28262504}.; PTM: Undergoes proteolytic degradation by SPG7. {ECO:0000269|PubMed:31097542}.
uniprot
proteins
protein_family
MCU (TC 1.A.77) family
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15164054
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21685886
uniprot
proteins
pubmed
21685888
uniprot
proteins
pubmed
22605770
uniprot
proteins
pubmed
22822213
uniprot
proteins
pubmed
22829870
uniprot
proteins
pubmed
22904319
uniprot
proteins
pubmed
23051746
uniprot
proteins
pubmed
23101630
uniprot
proteins
pubmed
23178883
uniprot
proteins
pubmed
23246404
uniprot
proteins
pubmed
23755363
uniprot
proteins
pubmed
24231807
uniprot
proteins
pubmed
24332854
uniprot
proteins
pubmed
24430870
uniprot
proteins
pubmed
24560927
uniprot
proteins
pubmed
24800979
uniprot
proteins
pubmed
25254480
uniprot
proteins
pubmed
25254481
uniprot
proteins
pubmed
25603276
uniprot
proteins
pubmed
25764156
uniprot
proteins
pubmed
25944712
uniprot
proteins
pubmed
26341627
uniprot
proteins
pubmed
26903221
uniprot
proteins
pubmed
26976564
uniprot
proteins
pubmed
27099988
uniprot
proteins
pubmed
27135929
uniprot
proteins
pubmed
27184846
uniprot
proteins
pubmed
28262504
uniprot
proteins
pubmed
29954988
uniprot
proteins
pubmed
29995857
uniprot
proteins
pubmed
30454562
uniprot
proteins
pubmed
30638448
uniprot
proteins
pubmed
31080062
uniprot
proteins
pubmed
31097542
uniprot
proteins
pubmed
32494073
uniprot
proteins
pubmed
32762847
uniprot
proteins
pubmed
32862359
uniprot
proteins
pubmed
33296646
uniprot
proteins
pubmed
37036971
uniprot
proteins
pubmed
37126688
uniprot
proteins
sequence_length
351
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Mitochondrion inner membrane {ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:21685888, ECO:0000269|PubMed:23755363, ECO:0000269|PubMed:24231807, ECO:0000269|PubMed:27099988, ECO:0000305|PubMed:26341627, ECO:0000305|PubMed:31080062}; Multi-pass membrane protein {ECO:0000269|PubMed:21685886, ECO:0000269|PubMed:21685888, ECO:0000269|PubMed:24231807, ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073, ECO:0000269|PubMed:32762847, ECO:0000269|PubMed:32862359}.
uniprot
proteins
transmembrane_region
TRANSMEM 234..255; /note="Helical"; /evidence="ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073, ECO:0000269|PubMed:32762847, ECO:0000269|PubMed:32862359, ECO:0007744|PDB:6K7X, ECO:0007744|PDB:6K7Y, ECO:0007744|PDB:6O58, ECO:0007744|PDB:6O5B, ECO:0007744|PDB:6WDN, ECO:0007744|PDB:6WDO, ECO:0007744|PDB:6XJV, ECO:0007744|PDB:6XJX"; TRANSMEM 263..284; /note="Helical"; /evidence="ECO:0000269|PubMed:31080062, ECO:0000269|PubMed:32494073, ECO:0000269|PubMed:32762847, ECO:0000269|PubMed:32862359, ECO:0007744|PDB:6K7X, ECO:0007744|PDB:6K7Y, ECO:0007744|PDB:6O58, ECO:0007744|PDB:6O5B, ECO:0007744|PDB:6WDN, ECO:0007744|PDB:6WDO, ECO:0007744|PDB:6XJV, ECO:0007744|PDB:6XJX
uniprot
proteins