Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9M119L)

• DOT Name: NADH dehydrogenase 1 subunit C2 (NDUFC2)
• Synonyms: Complex I-B14.5b; CI-B14.5b; Human lung cancer oncogene 1 protein; HLC-1; NADH-ubiquinone oxidoreductase subunit B14.5b
• Gene Name: NDUFC2
• Related Disease:
  Acute coronary syndrome
  Colon carcinoma
  Squamous cell carcinoma
  Stroke
  Leigh syndrome
  Lung adenocarcinoma
  Mitochondrial disease
  Mitochondrial complex 1 deficiency, nuclear type 36
• UniProt ID: NDUC2_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF06374
• Sequence:
  MIARRNPEPLRFLPDEARSLPPPKLTDPRLLYIGFLGYCSGLIDNLIRRRPIATAGLHRQ
  LLYITAFFFAGYYLVKREDYLYAVRDREMFGYMKLHPEDFPEEDKKTYGEIFEKFHPIR
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis but required for the complex assembly. 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:
  Neutrophil degranulation (R-HSA-6798695)
  Complex I biogenesis (R-HSA-6799198)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS07729-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Stroke	DISX6UHX	Strong	Altered Expression	[4]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[5]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[6]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[5]
Mitochondrial complex 1 deficiency, nuclear type 36	DIS5WUK9	Limited	Unknown	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase 1 subunit C2 (NDUFC2) affects the response to substance of Vinblastine.	[18]

10 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 subunit C2 (NDUFC2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase 1 subunit C2 (NDUFC2).	[17]

References

• [1] The reduction of NDUFC2 expression is associated with mitochondrial impairment in circulating mononuclear cells of patients with acute coronary syndrome.Int J Cardiol. 2019 Jul 1;286:127-133. doi: 10.1016/j.ijcard.2019.02.027. Epub 2019 Feb 14.
• [2] Protein analysis of NCA-50 shows identity to NCA cDNA deduced sequences and indicates posttranslational modifications.Biochem Biophys Res Commun. 1988 Jun 30;153(3):1105-15. doi: 10.1016/s0006-291x(88)81342-1.
• [3] REG I gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms.Oncol Rep. 2013 Dec;30(6):2625-31. doi: 10.3892/or.2013.2739. Epub 2013 Sep 19.
• [4] Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease.J Am Heart Assoc. 2016 Feb 17;5(2):e002701. doi: 10.1161/JAHA.115.002701.
• [5] 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.
• [6] Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.Oncol Lett. 2018 Feb;15(2):1549-1558. doi: 10.3892/ol.2017.7517. Epub 2017 Dec 5.
• [7] Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I. EMBO Mol Med. 2020 Nov 6;12(11):e12619. doi: 10.15252/emmm.202012619. Epub 2020 Sep 24.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [17] 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.
• [18] 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.