Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4)
• Synonyms: Complex I-18 kDa; CI-18 kDa; Complex I-AQDQ; CI-AQDQ; NADH-ubiquinone oxidoreductase 18 kDa subunit
• Gene Name: NDUFS4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Leigh syndrome
  Triple negative breast cancer
  Atrial fibrillation
  Depression
  Insomnia
  Marginal zone lymphoma
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Nasopharyngitis
  Non-insulin dependent diabetes
  Parkinson disease
  Respiratory disease
  rubella
  Systemic lupus erythematosus
  Tuberculosis
  Obsolete mitochondrial complex I deficiency, nuclear type
  Portal hypertension, noncirrhotic
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
  Ankylosing spondylitis
  Blindness
  Generalized anxiety disorder
  High blood pressure
  Lactic acidosis
  Nervous system disease
  Parkinsonian disorder
• UniProt ID: NDUS4_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF04800
• Sequence:
  MAAVSMSVVLRQTLWRRRAVAVAALSVSRVPTRSLRTSTWRLAQDQTQDTQLITVDEKLD
  ITTLTGVPEEHIKTRKVRIFVPARNNMQSGVNNTKKWKMEFDTRERWENPLMGWASTADP
  LSNMVLTFSTKEDAVSFAEKNGWSYDIEERKVPKPKSKSYGANFSWNKRTRVSTK
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
• 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:ENSG00000164258-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Triple negative breast cancer	DISAMG6N	Definitive	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Insomnia	DIS0AFR7	Strong	Genetic Variation	[5]
Marginal zone lymphoma	DISLZ4AO	Strong	Biomarker	[6]
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Strong	Autosomal recessive	[7]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[8]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Biomarker	[9]
Nasopharyngitis	DISVLL0V	Strong	Genetic Variation	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[11]
Respiratory disease	DISGGAGJ	Strong	Genetic Variation	[12]
rubella	DISXUI9P	Strong	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[14]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[15]
Obsolete mitochondrial complex I deficiency, nuclear type	DISO3LL4	Moderate	Autosomal recessive	[16]
Portal hypertension, noncirrhotic	DISZZMLV	moderate	Biomarker	[17]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[18]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[19]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[20]
Blindness	DISTIM10	Limited	Biomarker	[21]
Generalized anxiety disorder	DISPSQCW	Limited	Genetic Variation	[22]
High blood pressure	DISY2OHH	Limited	Biomarker	[23]
Lactic acidosis	DISZI1ZK	Limited	Biomarker	[24]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[25]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[26]

2 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 dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[31]
Selenium	DM25CGV	Approved	Selenium decreases the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[32]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4).	[34]

References

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• [4] Isoflurane disrupts excitatory neurotransmitter dynamics via inhibition of mitochondrial complex I.Br J Anaesth. 2018 May;120(5):1019-1032. doi: 10.1016/j.bja.2018.01.036. Epub 2018 Mar 13.
• [5] Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?.Int J Clin Pract. 2017 Nov;71(11). doi: 10.1111/ijcp.13030. Epub 2017 Oct 12.
• [6] An open-label phase 2 trial of entospletinib in indolent non-Hodgkin lymphoma and mantle cell lymphoma.Br J Haematol. 2019 Jan;184(2):215-222. doi: 10.1111/bjh.15552. Epub 2018 Sep 5.
• [7] Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. Biochem Biophys Res Commun. 2000 Aug 18;275(1):63-8. doi: 10.1006/bbrc.2000.3257.
• [8] Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome.Am J Physiol Lung Cell Mol Physiol. 2019 Feb 1;316(2):L391-L399. doi: 10.1152/ajplung.00419.2018. Epub 2018 Dec 6.
• [9] Mitochondrial complex III stabilizes complex I in the absence of NDUFS4 to provide partial activity.Hum Mol Genet. 2012 Jan 1;21(1):115-20. doi: 10.1093/hmg/ddr446. Epub 2011 Sep 28.
• [10] The global prevalence of tobacco use in type 2 diabetes mellitus patients: A systematic review and meta-analysis.Diabetes Res Clin Pract. 2019 Aug;154:52-65. doi: 10.1016/j.diabres.2019.05.035. Epub 2019 Jun 14.
• [11] Age-dependent accumulation of oligomeric SNCA/-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA).Autophagy. 2020 Feb;16(2):347-370. doi: 10.1080/15548627.2019.1603545. Epub 2019 Apr 14.
• [12] Identification of a deletion in the NDUFS4 gene using array-comparative genomic hybridization in a patient with suspected mitochondrial respiratory disease.Gene. 2014 Feb 10;535(2):376-9. doi: 10.1016/j.gene.2013.10.074. Epub 2013 Dec 1.
• [13] Congenital viral infections in England over five decades: a population-based observational study.Lancet Infect Dis. 2020 Feb;20(2):220-229. doi: 10.1016/S1473-3099(19)30416-5. Epub 2019 Nov 7.
• [14] Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry.J Rheumatol. 2013 Jun;40(6):842-9. doi: 10.3899/jrheum.120989. Epub 2013 May 1.
• [15] Mortality in children diagnosed with tuberculosis: a systematic review and meta-analysis.Lancet Infect Dis. 2017 Mar;17(3):285-295. doi: 10.1016/S1473-3099(16)30474-1. Epub 2016 Dec 8.
• [16] 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.
• [17] Spleen stiffness measurements using point shear wave elastography detects noncirrhotic portal hypertension in human immunodeficiency virus.Medicine (Baltimore). 2019 Nov;98(47):e17961. doi: 10.1097/MD.0000000000017961.
• [18] Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet. 1998 Feb;62(2):262-8. doi: 10.1086/301716.
• [19] A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family. J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S461-7. doi: 10.1007/s10545-008-1049-9. Epub 2008 Dec 26.
• [20] Identification of potential target genes for ankylosing spondylitis treatment.Medicine (Baltimore). 2018 Feb;97(8):e9760. doi: 10.1097/MD.0000000000009760.
• [21] Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model.Brain Res. 2017 Feb 15;1657:232-244. doi: 10.1016/j.brainres.2016.12.019. Epub 2016 Dec 24.
• [22] Prediction of type 1 diabetes among siblings of affected children and in the general population.Diabetologia. 2007 Nov;50(11):2272-5. doi: 10.1007/s00125-007-0799-5. Epub 2007 Sep 4.
• [23] Understanding racial disparities in renal cell carcinoma incidence: estimates of population attributable risk in two US populations.Cancer Causes Control. 2020 Jan;31(1):85-93. doi: 10.1007/s10552-019-01248-1. Epub 2019 Nov 28.
• [24] Targeting NAD(+) Metabolism as Interventions for Mitochondrial Disease.Sci Rep. 2019 Feb 28;9(1):3073. doi: 10.1038/s41598-019-39419-4.
• [25] Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation.Cell Metab. 2019 Oct 1;30(4):824-832.e3. doi: 10.1016/j.cmet.2019.07.006. Epub 2019 Aug 8.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Hydrogen peroxide induces adaptive response and differential gene expression in human embryo lung fibroblast cells. Environ Toxicol. 2014 Apr;29(4):478-85. doi: 10.1002/tox.21775. Epub 2012 Apr 7.
• [32] 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.
• [33] 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.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.