Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8)
• Synonyms: EC 7.1.1.2; Complex I-23kD; CI-23kD; NADH-ubiquinone oxidoreductase 23 kDa subunit; TYKY subunit
• Gene Name: NDUFS8
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Mitochondrial complex 1 deficiency, nuclear type 2
  Mitochondrial disease
  Neoplasm
  Non-small-cell lung cancer
  Leigh syndrome
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
  Osteoarthritis
• UniProt ID: NDUS8_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF12838
• Sequence:
  MRCLTTPMLLRALAQAARAGPPGGRSLHSSAVAATYKYVNMQDPEMDMKSVTDRAARTLL
  WTELFRGLGMTLSYLFREPATINYPFEKGPLSPRFRGEHALRRYPSGEERCIACKLCEAI
  CPAQAITIEAEPRADGSRRTTRYDIDMTKCIYCGFCQEACPVDAIVEGPNFEFSTETHEE
  LLYNKEKLLNNGDKWEAEIAANIQADYLYR
• Function: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly of complex I.
• Tissue Specificity: Expressed in all tissues with the highest level in heart and skeletal muscle and the lowest level in lung.
• 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:
  Complex I biogenesis (R-HSA-6799198)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS03332-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Mitochondrial complex 1 deficiency, nuclear type 2	DIS1L5IG	Strong	Autosomal recessive	[4]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[6]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[7]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[4]
Osteoarthritis	DIS05URM	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8) affects the response to substance of Cisplatin.	[24]
Methotrexate	DM2TEOL	Approved	NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8) affects the response to substance of Methotrexate.	[24]
Paclitaxel	DMLB81S	Approved	NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8) affects the response to substance of Paclitaxel.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of NADH dehydrogenase iron-sulfur protein 8, mitochondrial (NDUFS8).	[23]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma.Int J Urol. 2019 Sep;26(9):910-916. doi: 10.1111/iju.14040. Epub 2019 Jul 7.
• [3] The opposite prognostic effect of NDUFS1 and NDUFS8 in lung cancer reflects the oncojanus role of mitochondrial complex I.Sci Rep. 2016 Aug 12;6:31357. doi: 10.1038/srep31357.
• [4] Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology. 2004 May 25;62(10):1899-901. doi: 10.1212/01.wnl.0000125251.56131.65.
• [5] Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency.Glia. 2018 Apr;66(4):874-888. doi: 10.1002/glia.23290. Epub 2017 Dec 29.
• [6] 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.
• [7] Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet. 2012 Apr;49(4):277-83. doi: 10.1136/jmedgenet-2012-100846.
• [8] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [12] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [16] Antineoplastic effects of decitabine, an inhibitor of DNA promoter methylation, in adrenocortical carcinoma cells. Arch Surg. 2010 Mar;145(3):226-32. doi: 10.1001/archsurg.2009.292.
• [17] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [18] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.