Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBURQ3A)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10)
• Synonyms: Complex I-42kD; CI-42kD; NADH-ubiquinone oxidoreductase 42 kDa subunit
• Gene Name: NDUFA10
• Related Disease:
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 22
  High blood pressure
  Mitochondrial disease
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUAA_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF01712
• Sequence:
  MALRLLKLAATSASARVVAAGAQRVRGIHSSVQCKLRYGMWHFLLGDKASKRLTERSRVI
  TVDGNICTGKGKLAKEIAEKLGFKHFPEAGIHYPDSTTGDGKPLATDYNGNCSLEKFYDD
  PRSNDGNSYRLQSWLYSSRLLQYSDALEHLLTTGQGVVLERSIFSDFVFLEAMYNQGFIR
  KQCVDHYNEVKSVTICDYLPPHLVIYIDVPVPEVQRRIQKKGDPHEMKITSAYLQDIENA
  YKKTFLPEMSEKCEVLQYSAREAQDSKKVVEDIEYLKFDKGPWLKQDNRTLYHLRLLVQD
  KFEVLNYTSIPIFLPEVTIGAHQTDRVLHQFRELPGRKYSPGYNTEVGDKWIWLK
• 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:HS05385-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Strong	Autosomal recessive	[1]
Mitochondrial complex 1 deficiency, nuclear type 22	DISWF4HA	Strong	Autosomal recessive	[2]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[3]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10) decreases the response to substance of Afimoxifene.	[22]

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 NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[16]
Cocaine	DMSOX7I	Approved	Cocaine affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[17]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial (NDUFA10).	[19]

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] NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. Eur J Hum Genet. 2011 Mar;19(3):270-4. doi: 10.1038/ejhg.2010.204. Epub 2010 Dec 8.
• [3] Characterization of mitochondrial NADH dehydrogenase 1 subcomplex 10 variants in cardiac muscles from normal Wistar rats and spontaneously hypertensive rats: Implications in the pathogenesis of hypertension.Mol Med Rep. 2016 Jan;13(1):961-6. doi: 10.3892/mmr.2015.4607. Epub 2015 Nov 23.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [13] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [14] 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.
• [15] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction. Neuropharmacology. 2009 Jul;57(1):41-8. doi: 10.1016/j.neuropharm.2009.04.005. Epub 2009 Apr 22.
• [18] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [19] 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.
• [20] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [21] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.
• [22] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.