Details of Drug Off-Target (DOT)

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

• DOT Name: NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1)
• Synonyms: EC 7.1.1.2; Complex I-75kD; CI-75kD
• Gene Name: NDUFS1
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Leigh syndrome
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial disease
  Renal cell carcinoma
  Autism spectrum disorder
  Bipolar disorder
  Frontotemporal dementia
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Lung cancer
  Lung carcinoma
  Mitochondrial complex 1 deficiency, nuclear type 5
  Neoplasm
  Non-small-cell lung cancer
  Pervasive developmental disorder
  Testicular cancer
  Hypertrophic cardiomyopathy
  Schizophrenia
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
  Parkinsonian disorder
• UniProt ID: NDUS1_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF13510 ; PF00384 ; PF10588 ; PF09326
• Sequence:
  MLRIPVRKALVGLSKSPKGCVRTTATAASNLIEVFVDGQSVMVEPGTTVLQACEKVGMQI
  PRFCYHERLSVAGNCRMCLVEIEKAPKVVAACAMPVMKGWNILTNSEKSKKAREGVMEFL
  LANHPLDCPICDQGGECDLQDQSMMFGNDRSRFLEGKRAVEDKNIGPLVKTIMTRCIQCT
  RCIRFASEIAGVDDLGTTGRGNDMQVGTYIEKMFMSELSGNIIDICPVGALTSKPYAFTA
  RPWETRKTESIDVMDAVGSNIVVSTRTGEVMRILPRMHEDINEEWISDKTRFAYDGLKRQ
  RLTEPMVRNEKGLLTYTSWEDALSRVAGMLQSFQGKDVAAIAGGLVDAEALVALKDLLNR
  VDSDTLCTEEVFPTAGAGTDLRSNYLLNTTIAGVEEADVVLLVGTNPRFEAPLFNARIRK
  SWLHNDLKVALIGSPVDLTYTYDHLGDSPKILQDIASGSHPFSQVLKEAKKPMVVLGSSA
  LQRNDGAAILAAVSSIAQKIRMTSGVTGDWKVMNILHRIASQVAALDLGYKPGVEAIRKN
  PPKVLFLLGADGGCITRQDLPKDCFIIYQGHHGDVGAPIADVILPGAAYTEKSATYVNTE
  GRAQQTKVAVTPPGLAREDWKIIRALSEIAGMTLPYDTLDQVRNRLEEVSPNLVRYDDIE
  GANYFQQANELSKLVNQQLLADPLVPPQLTIKDFYMTDSISRASQTMAKCVKAVTEGAQA
  VEEPSIC
• 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 catalysing the entry and efficient transfer of electrons within complex I. Plays a key role in the assembly and stability of complex I and participates in the association of complex I with ubiquinol-cytochrome reductase complex (Complex III) to form supercomplexes.
• 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:HS00422-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Definitive	Altered Expression	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[3]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Renal cell carcinoma	DISQZ2X8	Definitive	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[7]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Mitochondrial complex 1 deficiency, nuclear type 5	DISY3WZU	Strong	Autosomal recessive	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[4]
Testicular cancer	DIS6HNYO	Strong	Altered Expression	[10]
Hypertrophic cardiomyopathy	DISQG2AI	moderate	Biomarker	[11]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[12]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[13]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[14]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[28]

14 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 NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[23]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[24]
Tramadol	DMRQD04	Approved	Tramadol decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[29]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[30]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[31]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1).	[32]

References

• [1] Systematic Expression Analysis of Mitochondrial Complex I Identifies NDUFS1 as a Biomarker in Clear-Cell Renal-Cell Carcinoma.Clin Genitourin Cancer. 2017 Aug;15(4):e551-e562. doi: 10.1016/j.clgc.2016.11.010. Epub 2016 Dec 1.
• [2] 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.
• [3] 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.
• [4] Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia.Eur Child Adolesc Psychiatry. 2010 May;19(5):441-8. doi: 10.1007/s00787-009-0074-z. Epub 2009 Nov 6.
• [5] Mitochondrial complex I and III mRNA levels in bipolar disorder.J Affect Disord. 2015 Sep 15;184:160-3. doi: 10.1016/j.jad.2015.05.060. Epub 2015 Jun 10.
• [6] Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.Lancet Neurol. 2018 Jun;17(6):548-558. doi: 10.1016/S1474-4422(18)30126-1. Epub 2018 Apr 30.
• [7] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [8] 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.
• [9] Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet. 2001 Jun;68(6):1344-52. doi: 10.1086/320603. Epub 2001 May 7.
• [10] Altered Molecular Pathways in the Proteome of Cryopreserved Sperm in Testicular Cancer Patients before Treatment.Int J Mol Sci. 2019 Feb 5;20(3):677. doi: 10.3390/ijms20030677.
• [11] An integrated approach to proteome analysis: identification of proteins associated with cardiac hypertrophy.Anal Biochem. 1998 Apr 10;258(1):1-18. doi: 10.1006/abio.1998.2566.
• [12] Genetic variant in NDUFS1 gene is associated with schizophrenia and negative symptoms in Han Chinese.J Hum Genet. 2015 Jan;60(1):11-6. doi: 10.1038/jhg.2014.94. Epub 2014 Oct 30.
• [13] Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Mol Genet Metab. 2010 Jul;100(3):251-6. doi: 10.1016/j.ymgme.2010.03.015. Epub 2010 Mar 21.
• [14] Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. Arch Neurol. 2005 Apr;62(4):659-61. doi: 10.1001/archneur.62.4.659.
• [15] Pathogenetic mechanisms in hereditary dysfunctions of complex I of the respiratory chain in neurological diseases.Biochim Biophys Acta. 2009 May;1787(5):502-17. doi: 10.1016/j.bbabio.2008.12.018. Epub 2009 Jan 10.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [21] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [22] Tea polyphenols ameliorates neural redox imbalance and mitochondrial dysfunction via mechanisms linking the key circadian regular Bmal1. Food Chem Toxicol. 2017 Dec;110:189-199. doi: 10.1016/j.fct.2017.10.031. Epub 2017 Oct 20.
• [23] 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.
• [24] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [25] Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells. Toxicology. 2016 Jun 1;359-360:1-10. doi: 10.1016/j.tox.2016.06.010. Epub 2016 Jun 15.
• [26] Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet. 2014 Apr 15;23(8):2106-19.
• [27] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] 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.
• [30] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [31] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [32] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.