Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDVH3QG)

• DOT Name: Cytochrome c oxidase subunit NDUFA4 (NDUFA4)
• Synonyms: Complex I-MLRQ; CI-MLRQ; NADH-ubiquinone oxidoreductase MLRQ subunit
• Gene Name: NDUFA4
• Related Disease:
  Cerebellar disorder
  Colorectal carcinoma
  Cytochrome-c oxidase deficiency disease
  Dandy-Walker syndrome
  Obsolete Leigh syndrome with leukodystrophy
  Leigh syndrome
  Neoplasm
• UniProt ID: NDUA4_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF06522
• Sequence:
  MLRQIIGQAKKHPSLIPLFVFIGTGATGATLYLLRLALFNPDVCWDRNNPEPWNKLGPND
  QYKFYSVNVDYSKLKKERPDF
• Function: Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix. NDUFA4 is required for complex IV maintenance.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
• BioCyc Pathway: MetaCyc:HS08711-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar disorder	DIS2O7WM	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[3]
Dandy-Walker syndrome	DIS4HC6W	Strong	Genetic Variation	[1]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[4]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[5]
Neoplasm	DISZKGEW	Limited	Biomarker	[6]

15 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 Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Cytochrome c oxidase subunit NDUFA4 (NDUFA4).	[21]

References

• [1] Prenatal diagnosis and molecular characterization of a novel locus for Dandy-Walker malformation on chromosome 7p21.3.Eur J Med Genet. 2012 Aug-Sep;55(8-9):472-5. doi: 10.1016/j.ejmg.2012.04.008. Epub 2012 May 19.
• [2] LncRNA MAFG-AS1 promotes the progression of colorectal cancer by sponging miR-147b and activation of NDUFA4.Biochem Biophys Res Commun. 2018 Nov 17;506(1):251-258. doi: 10.1016/j.bbrc.2018.10.112. Epub 2018 Oct 19.
• [3] NDUFA4 (Renamed COXFA4) Is a Cytochrome-c Oxidase Subunit.Trends Endocrinol Metab. 2018 Jul;29(7):452-454. doi: 10.1016/j.tem.2018.03.009. Epub 2018 Apr 7.
• [4] NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. Cell Rep. 2013 Jun 27;3(6):1795-805. doi: 10.1016/j.celrep.2013.05.005. Epub 2013 Jun 6.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization.Br J Cancer. 2001 Nov 2;85(9):1372-82. doi: 10.1054/bjoc.2001.2074.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.