MICU1
Domain
The EF-hand domains have high affinity for calcium and act as sensors of calcium levels (PubMed:23101630, PubMed:24560927).
The polybasic region mediates interaction with EMRE/SMDT1 and association with the uniplex complex.
Lysine and arginine residues in the K/R-ring mediate electrostatic interactions with MCU and play a key role in MCU inhibition in absence of calcium.
The C-helix plays a key role in mitochondrial calcium uptake, probably by mediating interaction with MICU2 (PubMed:24503055, PubMed:24514027).
Function
Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains (PubMed:20693986, PubMed:23101630, PubMed:23747253, PubMed:24313810, PubMed:24332854, PubMed:24503055, PubMed:24560927, PubMed:26341627, PubMed:26903221, PubMed:27099988, PubMed:28615291, PubMed:30454562, PubMed:30638448, PubMed:32494073, PubMed:32667285, PubMed:32762847, PubMed:32790952, PubMed:34463251, PubMed:36206740, PubMed:37036971, PubMed:37126688). MICU1 and MICU2 (or MICU3) form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium (PubMed:24560927, PubMed:26903221, PubMed:28615291, PubMed:32148862, PubMed:32494073, PubMed:32667285, PubMed:32762847, PubMed:32790952, PubMed:36206740, PubMed:37036971, PubMed:37126688). At low calcium levels, MICU1 occludes the pore of the MCU channel, preventing mitochondrial calcium uptake (PubMed:32494073, PubMed:32667285, 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 MCU channel (PubMed:32494073, PubMed:32667285, PubMed:32762847). Also required to protect against manganese toxicity by preventing manganese uptake by MCU: mechanistically, manganese-binding to its EF-hand domains does not induce any conformational change, maintaining MCU pore occlusion (PubMed:30082385, PubMed:30403999). Also acts as a barrier for inhibitors of the MCU channel, such as ruthenium red or its derivative Ru360 (PubMed:37244260). Acts as a regulator of mitochondrial cristae structure independently of its ability to regulate the mitochondrial calcium uniporter channel (PubMed:31427612, PubMed:37098122). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319). Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG (PubMed:16002733).
Isoform 6
Isoform that regulates mitochondrial calcium uniporter (MCU) in the skeletal muscle (By similarity). Compared to other isoforms, this isoform has higher affinity for calcium, promoting mitochondrial calcium uptake at lower calcium concentrations (By similarity). This allows a rapid response of mitochondrial metabolism and ensures sustained ATP production needed for resistance and strenuous exercise (By similarity).
Involvement in disease
Myopathy with extrapyramidal signs
MPXPS
An autosomal recessive disorder characterized by early-onset proximal muscle weakness with a static course and moderately to grossly elevated serum creatine kinase levels accompanied by learning difficulties. Most patients develop subtle extrapyramidal motor signs that progress to a debilitating disorder of involuntary movement with variable features, including chorea, tremor, dystonic posturing and orofacial dyskinesia. Additional variable features include ataxia, microcephaly, ophthalmoplegia, ptosis, optic atrophy and axonal peripheral neuropathy.
None
The disease is caused by variants affecting the gene represented in this entry. The complex phenotype is due to alterations in mitochondrial calcium signaling characterized by increased mitochondrial Ca(2+) load (PubMed:24336167).
An homozygous partial MICU1 deletion is responsible for a disorder manifesting in childhood with fatigue, lethargy and muscle weakness. The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation at Ser-122 by AKT1 impairs its maturation and stability.
Asymmetric dimethylation at Arg-455 by PRMT1 decreases the calcium sensitivity of MICU1 by promoting interaction with UCP2.
Degraded by YME1L1 when not complexed as homodimer or heterodimer (PubMed:36206740). Not degraded when complexed as homodimer or heterodimer; the presence of the interchain disulfide bond protecting MICU1 from degradation by YME1L1 (PubMed:36206740).
Sequence Similarities
Belongs to the MICU1 family. MICU1 subfamily.
Tissue Specificity
Expressed in epithelial cell lines. Strongly expressed in epidermal keratinocytes and dermal endothelial cells.
Cellular localization
- Mitochondrion intermembrane space
- Mitochondrion inner membrane
- Recruited to the mitochondrial inner membrane by EMRE/SMDT1 (PubMed:30454562). Also localizes to mitochondrial cristae junctions (PubMed:31427612).
- Isoform 6
- Mitochondrion intermembrane space
- Mitochondrion inner membrane
Alternative names
CALC, CBARA1, MICU1, Atopy-related autoantigen CALC, Calcium-binding atopy-related autoantigen 1, ara CALC