Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBO0YKI)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8)
• Synonyms: Complex I-19kD; CI-19kD; Complex I-PGIV; CI-PGIV; NADH-ubiquinone oxidoreductase 19 kDa subunit
• Gene Name: NDUFA8
• Related Disease:
  Mitochondrial complex 1 deficiency, nuclear type 37
  Mitochondrial disease
• UniProt ID: NDUA8_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF06747
• Sequence:
  MPGIVELPTLEELKVDEVKISSAVLKAAAHHYGAQCDKPNKEFMLCRWEEKDPRRCLEEG
  KLVNKCALDFFRQIKRHCAEPFTEYWTCIDYTGQQLFRHCRKQQAKFDECVLDKLGWVRP
  DLGELSKVTKVKTDRPLPENPYHSRPRPDPSPEIEGDLQPATHGSRFYFWTK
• 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:HS04297-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex 1 deficiency, nuclear type 37	DIS8UZOE	Limited	Unknown	[1]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[8]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 8 (NDUFA8).	[13]

References

• [1] Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):136-47. doi: 10.1016/j.bbabio.2004.09.006.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [9] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [10] 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.
• [11] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.