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
• 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]

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]

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.