Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium uniporter protein, mitochondrial (MCU)
• Synonyms: HsMCU; Coiled-coil domain-containing protein 109A
• Gene Name: MCU
• Related Disease:
  Neoplasm
  T-cell acute lymphoblastic leukaemia
  Type-1 diabetes
  Advanced cancer
  Alzheimer disease
  Cardiac failure
  Chagas disease
  Congestive heart failure
  Influenza
  Lymphoproliferative syndrome
  Nephropathy
  Obesity
  Parkinson disease
  Pulmonary arterial hypertension
  Autosomal dominant optic atrophy, classic form
  Coronary atherosclerosis
  High blood pressure
  Myocardial ischemia
  Pulmonary fibrosis
  Amyotrophic lateral sclerosis
  Neuroblastoma
  Breast cancer
  Breast carcinoma
  Young-onset Parkinson disease
• UniProt ID: MCU_HUMAN
• PDB ID: 4XSJ; 4XTB; 5BZ6; 5KUE; 5KUG; 5KUI; 5KUJ; 6JG0; 6K7X; 6K7Y; 6KVX; 6O58; 6O5B; 6WDN; 6WDO; 6XJV; 6XJX
• Pfam ID: PF04678
• Sequence:
  MAAAAGRSLLLLLSSRGGGGGGAGGCGALTAGCFPGLGVSRHRQQQHHRTVHQRIASWQN
  LGAVYCSTVVPSDDVTVVYQNGLPVISVRLPSRRERCQFTLKPISDSVGVFLRQLQEEDR
  GIDRVAIYSPDGVRVAASTGIDLLLLDDFKLVINDLTYHVRPPKRDLLSHENAATLNDVK
  TLVQQLYTTLCIEQHQLNKERELIERLEDLKEQLAPLEKVRIEISRKAEKRTTLVLWGGL
  AYMATQFGILARLTWWEYSWDIMEPVTYFITYGSAMAMYAYFVMTRQEYVYPEARDRQYL
  LFFHKGAKKSRFDLEKYNQLKDAIAQAEMDLKRLRDPLQVHLPLRQIGEKD
• Function: Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria. Constitutes the pore-forming and calcium-conducting subunit of the uniporter complex (uniplex). Activity is regulated by MICU1 and MICU2. At low Ca(2+) levels MCU activity is down-regulated by MICU1 and MICU2; at higher Ca(2+) levels MICU1 increases MCU activity. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes. 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. participates in mitochondrial permeability transition during ischemia-reperfusion injury. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults. Regulates synaptic vesicle endocytosis kinetics in central nerve terminal. Involved in antigen processing and presentation.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Cellular senescence (hsa04218)
  NOD-like receptor sig.ling pathway (hsa04621)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• 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
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[2]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Chagas disease	DIS8KNVF	Strong	Biomarker	[7]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[9]
Nephropathy	DISXWP4P	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Parkinson disease	DISQVHKL	Strong	Biomarker	[12]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[13]
Autosomal dominant optic atrophy, classic form	DISXUAV9	moderate	Altered Expression	[14]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[14]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[15]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[14]
Pulmonary fibrosis	DISQKVLA	moderate	Altered Expression	[16]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Altered Expression	[17]
Neuroblastoma	DISVZBI4	Disputed	Altered Expression	[18]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[19]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[19]
Young-onset Parkinson disease	DIS05LFS	Limited	Biomarker	[20]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Calcium uniporter protein, mitochondrial (MCU).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium uniporter protein, mitochondrial (MCU).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcium uniporter protein, mitochondrial (MCU).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium uniporter protein, mitochondrial (MCU).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium uniporter protein, mitochondrial (MCU).	[25]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calcium uniporter protein, mitochondrial (MCU).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium uniporter protein, mitochondrial (MCU).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calcium uniporter protein, mitochondrial (MCU).	[28]

References

• [1] Mitochondrial calcium uniporter complex modulation in cancerogenesis.Cell Cycle. 2019 May;18(10):1068-1083. doi: 10.1080/15384101.2019.1612698. Epub 2019 May 10.
• [2] Epstein-Barr Virus-associated Mucocutaneous Ulcer in a Patient With T-Cell Acute Lymphoblastic Leukemia: Importance of Accurate Diagnosis and Conservative Management.J Pediatr Hematol Oncol. 2017 Aug;39(6):e338-e341. doi: 10.1097/MPH.0000000000000709.
• [3] Transport of Ca(2+) and Ca(2+)-Dependent Permeability Transition in Rat Liver Mitochondria under the Streptozotocin-Induced Type I Diabetes.Cells. 2019 Aug 30;8(9):1014. doi: 10.3390/cells8091014.
• [4] New insights into the role of mitochondrial calcium homeostasis in cell migration.Biochem Biophys Res Commun. 2018 May 27;500(1):75-86. doi: 10.1016/j.bbrc.2017.05.039. Epub 2017 May 8.
• [5] Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer's disease.Acta Neuropsychiatr. 2020 Apr;32(2):65-71. doi: 10.1017/neu.2019.39. Epub 2019 Dec 26.
• [6] Mitochondrial calcium uniporter inhibition provides cardioprotection in pressure overload-induced heart failure through autophagy enhancement.Int J Cardiol. 2018 Nov 15;271:161-168. doi: 10.1016/j.ijcard.2018.05.054. Epub 2018 May 20.
• [7] The mitochondrial calcium uniporter complex in trypanosomes.Cell Biol Int. 2018 Jun;42(6):656-663. doi: 10.1002/cbin.10928. Epub 2018 Jan 25.
• [8] An Exhaustive Search Algorithm to Aid NMR-Based Structure Determination of Rotationally Symmetric Transmembrane Oligomers.Sci Rep. 2017 Dec 12;7(1):17373. doi: 10.1038/s41598-017-17639-w.
• [9] EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.Am J Surg Pathol. 2014 Nov;38(11):1522-9. doi: 10.1097/PAS.0000000000000282.
• [10] IP(3)R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.BMC Nephrol. 2018 Jun 15;19(1):140. doi: 10.1186/s12882-018-0940-3.
• [11] MCU-knockdown attenuates high glucose-induced inflammation through regulating MAPKs/NF-B pathways and ROS production in HepG2 cells.PLoS One. 2018 Apr 30;13(4):e0196580. doi: 10.1371/journal.pone.0196580. eCollection 2018.
• [12] Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease.Biol Open. 2019 Oct 15;8(10):bio044347. doi: 10.1242/bio.044347.
• [13] MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype.Am J Respir Crit Care Med. 2017 Feb 15;195(4):515-529. doi: 10.1164/rccm.201604-0814OC.
• [14] MCU Up-regulation contributes to myocardial ischemia-reperfusion Injury through calpain/OPA-1-mediated mitochondrial fusion/mitophagy Inhibition.J Cell Mol Med. 2019 Nov;23(11):7830-7843. doi: 10.1111/jcmm.14662. Epub 2019 Sep 9.
• [15] The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation.Int J Biochem Cell Biol. 2016 Sep;78:307-314. doi: 10.1016/j.biocel.2016.07.018. Epub 2016 Jul 25.
• [16] Mitochondrial calcium uniporter regulates PGC-1 expression to mediate metabolic reprogramming in pulmonary fibrosis.Redox Biol. 2019 Sep;26:101307. doi: 10.1016/j.redox.2019.101307. Epub 2019 Aug 25.
• [17] Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93A(hSOD1) mice.Neurobiol Aging. 2019 Mar;75:209-222. doi: 10.1016/j.neurobiolaging.2018.11.019. Epub 2018 Nov 23.
• [18] High Glucose Enhances Bupivacaine-Induced Neurotoxicity via MCU-Mediated Oxidative Stress in SH-SY5Y Cells.Oxid Med Cell Longev. 2019 Feb 18;2019:7192798. doi: 10.1155/2019/7192798. eCollection 2019.
• [19] Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect.Oncotarget. 2017 Jul 31;8(48):83831-83844. doi: 10.18632/oncotarget.19747. eCollection 2017 Oct 13.
• [20] Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1(-/-) zebrafish.Eur J Neurosci. 2017 Feb;45(4):528-535. doi: 10.1111/ejn.13473. Epub 2016 Dec 28.
• [21] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [22] 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.
• [23] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] 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.
• [26] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [27] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [28] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.