Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1)
• Synonyms: Complex I-MWFE; CI-MWFE; NADH-ubiquinone oxidoreductase MWFE subunit
• Gene Name: NDUFA1
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Obsolete mitochondrial complex I deficiency, nuclear type
  Basal cell carcinoma
  Huntington disease
  Leber hereditary optic neuropathy
  MELAS syndrome
  Mitochondrial complex 1 deficiency, nuclear type 12
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Parkinson disease
  Leigh syndrome
  Mitochondrial myopathy
  Mitochondrial complex I deficiency
  Optic nerve disorder
• UniProt ID: NDUA1_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF15879
• Sequence:
  MWFEILPGLSVMGVCLLIPGLATAYIHRFTNGGKEKRVAHFGYHWSLMERDRRISGVDRY
  YVSKGLENID
• 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.
• Tissue Specificity: Primarily expressed in heart and skeletal muscle.
• 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:HS04875-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 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	X-linked	[1]
Obsolete mitochondrial complex I deficiency, nuclear type	DISO3LL4	Definitive	X-linked recessive	[1]
Basal cell carcinoma	DIS7PYN3	Strong	Altered Expression	[2]
Huntington disease	DISQPLA4	Strong	Biomarker	[3]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[4]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[4]
Mitochondrial complex 1 deficiency, nuclear type 12	DISVVUSK	Strong	X-linked	[5]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[6]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[7]
Parkinson disease	DISQVHKL	Strong	Biomarker	[8]
Leigh syndrome	DISWQU45	Moderate	X-linked	[9]
Mitochondrial myopathy	DIS9SA7V	moderate	Genetic Variation	[10]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[7]
Optic nerve disorder	DISSOQM8	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1) affects the response to substance of Paclitaxel.	[28]
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1) affects the response to substance of Vinblastine.	[28]

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 1 alpha subcomplex subunit 1 (NDUFA1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[19]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[26]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 1 (NDUFA1).	[27]

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] Downregulation of NDUFA1 and other oxidative phosphorylation-related genes is a consistent feature of basal cell carcinoma.Exp Dermatol. 2005 May;14(5):336-48. doi: 10.1111/j.0906-6705.2005.00278.x.
• [3] A single-subunit NADH-quinone oxidoreductase renders resistance to mammalian nerve cells against complex I inhibition.Mol Ther. 2002 Sep;6(3):336-41. doi: 10.1006/mthe.2002.0674.
• [4] The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I.Hum Mol Genet. 2006 Sep 1;15(17):2543-52. doi: 10.1093/hmg/ddl176. Epub 2006 Jul 18.
• [5] SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. Ann Neurol. 2004 Aug;56(2):182-91. doi: 10.1002/ana.20175.
• [6] An X-chromosome linked mouse model (Ndufa1(S55A)) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases.Neurochem Int. 2017 Oct;109:78-93. doi: 10.1016/j.neuint.2017.05.003. Epub 2017 May 12.
• [7] X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007 Jan;61(1):73-83. doi: 10.1002/ana.21036.
• [8] Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease.Neurochem Res. 2004 Mar;29(3):569-77. doi: 10.1023/b:nere.0000014827.94562.4b.
• [9] 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.
• [10] Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Am J Hum Genet. 2000 Jun;66(6):1900-4. doi: 10.1086/302927. Epub 2000 Apr 17.
• [11] Suppression of complex I gene expression induces optic neuropathy.Ann Neurol. 2003 Feb;53(2):198-205. doi: 10.1002/ana.10426.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [19] 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.
• [20] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [26] 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.
• [27] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [28] 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.