Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS7N0LE)

DOT Name Calcium uptake protein 1, mitochondrial (MICU1)
Synonyms Atopy-related autoantigen CALC; ara CALC; Calcium-binding atopy-related autoantigen 1; allergen Hom s 4
Gene Name MICU1
Related Disease
Proximal myopathy with extrapyramidal signs ( )
Advanced cancer ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Bacterial infection ( )
Epithelial ovarian cancer ( )
Head-neck squamous cell carcinoma ( )
Movement disorder ( )
Myopathy ( )
Neoplasm ( )
Neuromuscular disease ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Pancreatic cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Melanoma ( )
Hyperglycemia ( )
Hyperlipidemia ( )
Carcinoma ( )
Cardiomyopathy ( )
Nervous system disease ( )
Type-1/2 diabetes ( )
Young-onset Parkinson disease ( )
UniProt ID
MICU1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4NSC; 4NSD; 6K7Y; 6LB7; 6LB8; 6LE5; 6WDN; 6WDO; 6XJV; 6XJX; 6XQN; 6XQO
Pfam ID
PF13202 ; PF13833
Sequence
MFRLNSLSALAELAVGSRWYHGGSQPIQIRRRLMMVAFLGASAVTASTGLLWKRAHAESP
PCVDNLKSDIGDKGKNKDEGDVCNHEKKTADLAPHPEEKKKKRSGFRDRKVMEYENRIRA
YSTPDKIFRYFATLKVISEPGEAEVFMTPEDFVRSITPNEKQPEHLGLDQYIIKRFDGKK
ISQEREKFADEGSIFYTLGECGLISFSDYIFLTTVLSTPQRNFEIAFKMFDLNGDGEVDM
EEFEQVQSIIRSQTSMGMRHRDRPTTGNTLKSGLCSALTTYFFGADLKGKLTIKNFLEFQ
RKLQHDVLKLEFERHDPVDGRITERQFGGMLLAYSGVQSKKLTAMQRQLKKHFKEGKGLT
FQEVENFFTFLKNINDVDTALSFYHMAGASLDKVTMQQVARTVAKVELSDHVCDVVFALF
DCDGNGELSNKEFVSIMKQRLMRGLEKPKDMGFTRLMQAMWKCAQETAWDFALPKQ
Function
Key regulator of mitochondrial calcium uniporter (MCU) that senses calcium level via its EF-hand domains. MICU1 and MICU2 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium. MICU1 acts both as an activator or inhibitor of mitochondrial calcium uptake. Acts as a gatekeeper of MCU at low concentration of calcium, preventing channel opening. Enhances MCU opening at high calcium concentration, allowing a rapid response of mitochondria to calcium signals generated in the cytoplasm. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG.
Tissue Specificity Expressed in epithelial cell lines. Strongly expressed in epidermal keratinocytes and dermal endothelial cells.
Reactome Pathway
Processing of SMDT1 (R-HSA-8949664 )
Mitochondrial calcium ion transport (R-HSA-8949215 )

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Proximal myopathy with extrapyramidal signs DISRE1CN Definitive Autosomal recessive [1]
Advanced cancer DISAT1Z9 Strong Biomarker [2]
Arteriosclerosis DISK5QGC Strong Biomarker [3]
Atherosclerosis DISMN9J3 Strong Biomarker [3]
Bacterial infection DIS5QJ9S Strong Altered Expression [4]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [5]
Head-neck squamous cell carcinoma DISF7P24 Strong Altered Expression [6]
Movement disorder DISOJJ2D Strong Genetic Variation [7]
Myopathy DISOWG27 Strong Biomarker [7]
Neoplasm DISZKGEW Strong Posttranslational Modification [2]
Neuromuscular disease DISQTIJZ Strong Genetic Variation [8]
Ovarian cancer DISZJHAP Strong Biomarker [5]
Ovarian neoplasm DISEAFTY Strong Biomarker [5]
Pancreatic cancer DISJC981 Strong Biomarker [9]
Breast cancer DIS7DPX1 moderate Altered Expression [10]
Breast carcinoma DIS2UE88 moderate Altered Expression [10]
Melanoma DIS1RRCY moderate Biomarker [11]
Hyperglycemia DIS0BZB5 Disputed Altered Expression [12]
Hyperlipidemia DIS61J3S Disputed Altered Expression [12]
Carcinoma DISH9F1N Limited Altered Expression [13]
Cardiomyopathy DISUPZRG Limited Altered Expression [12]
Nervous system disease DISJ7GGT Limited Biomarker [14]
Type-1/2 diabetes DISIUHAP Limited Altered Expression [12]
Young-onset Parkinson disease DIS05LFS Limited Biomarker [15]
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⏷ Show the Full List of 24 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [16]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [17]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [18]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [19]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [20]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [21]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [22]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Calcium uptake protein 1, mitochondrial (MICU1). [23]
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⏷ Show the Full List of 8 Drug(s)

References

1 Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
2 Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca(2+) levels and tumor growth.EMBO J. 2019 Jan 15;38(2):e99435. doi: 10.15252/embj.201899435. Epub 2018 Nov 30.
3 A novel ultrasound-based vascular calcification score (CALCS) to detect subclinical atherosclerosis.Eur Rev Med Pharmacol Sci. 2018 Feb;22(3):736-742. doi: 10.26355/eurrev_201802_14304.
4 Role of calcium in lipopolysaccharide-induced calcitonin gene expression in human adipocytes. Innate Immun. 2011 Aug;17(4):403-13. doi: 10.1177/1753425910377100. Epub 2010 Aug 3.
5 MICU1 drives glycolysis and chemoresistance in ovarian cancer.Nat Commun. 2017 May 22;8:14634. doi: 10.1038/ncomms14634.
6 Targeting EZH2 regulates tumor growth and apoptosis through modulating mitochondria dependent cell-death pathway in HNSCC.Oncotarget. 2015 Oct 20;6(32):33720-32. doi: 10.18632/oncotarget.5606.
7 Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet. 2014 Feb;46(2):188-93. doi: 10.1038/ng.2851. Epub 2013 Dec 15.
8 Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1.Cell Rep. 2019 Oct 29;29(5):1274-1286.e6. doi: 10.1016/j.celrep.2019.09.063.
9 Loss of heterozygosity at the calcium regulation gene locus on chromosome 10q in human pancreatic cancer.Asian Pac J Cancer Prev. 2015;16(6):2489-93. doi: 10.7314/apjcp.2015.16.6.2489.
10 Is calcitonin an active hormone in the onset and prevention of hypocalcemia in dairy cattle?.J Dairy Sci. 2016 Apr;99(4):3023-3030. doi: 10.3168/jds.2015-10229. Epub 2016 Feb 3.
11 RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling.Oncotarget. 2015 Oct 6;6(30):29614-25. doi: 10.18632/oncotarget.4868.
12 MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca(2+)-Dependent Antioxidant Response.Diabetes. 2017 Jun;66(6):1586-1600. doi: 10.2337/db16-1237. Epub 2017 Mar 14.
13 Mitochondrial calcium uniporter activity is dispensable for MDA-MB-231 breast carcinoma cell survival.PLoS One. 2014 May 6;9(5):e96866. doi: 10.1371/journal.pone.0096866. eCollection 2014.
14 MICU1 Confers Protection from MCU-Dependent Manganese Toxicity.Cell Rep. 2018 Nov 6;25(6):1425-1435.e7. doi: 10.1016/j.celrep.2018.10.037.
15 Parkin-dependent regulation of the MCU complex component MICU1.Sci Rep. 2018 Sep 21;8(1):14199. doi: 10.1038/s41598-018-32551-7.
16 The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
17 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
18 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
19 The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
20 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
21 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
22 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
23 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.