Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWJ5B9M)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4)
• Synonyms: Hormone-regulated proliferation-associated protein of 20 kDa
• Gene Name: NDUFAF4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Mitochondrial encephalomyopathy
  Breast neoplasm
  Mitochondrial complex 1 deficiency, nuclear type 15
  Mitochondrial disease
  Mitochondrial complex I deficiency
  Leigh syndrome
• UniProt ID: NDUF4_HUMAN
• Pfam ID: PF06784
• Sequence:
  MGALVIRGIRNFNLENRAEREISKMKPSVAPRHPSTNSLLREQISLYPEVKGEIARKDEK
  LLSFLKDVYVDSKDPVSSLQVKAAETCQEPKEFRLPKDHHFDMINIKSIPKGKISIVEAL
  TLLNNHKLFPETWTAEKIMQEYQLEQKDVNSLLKYFVTFEVEIFPPEDKKAIRSK
• Function: Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). May be involved in cell proliferation and survival of hormone-dependent tumor cells. May be a regulator of breast tumor cell invasion.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Mitochondrial encephalomyopathy	DISA6PTN	Definitive	Genetic Variation	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Mitochondrial complex 1 deficiency, nuclear type 15	DIS3VT2Q	Strong	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[3]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[4]

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 assembly factor 4 (NDUFAF4).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 4 (NDUFAF4).	[16]

References

• [1] C6ORF66 is an assembly factor of mitochondrial complex I. Am J Hum Genet. 2008 Jan;82(1):32-8. doi: 10.1016/j.ajhg.2007.08.003.
• [2] HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion.Oncogene. 2007 Mar 15;26(12):1780-8. doi: 10.1038/sj.onc.1209980. Epub 2006 Sep 25.
• [3] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.