Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4MCB6W)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3)
• Gene Name: NDUFAF3
• Related Disease:
  Mitochondrial disease
  Breast neoplasm
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 18
  Leigh syndrome with cardiomyopathy
  Mitochondrial complex I deficiency
• UniProt ID: NDUF3_HUMAN
• Pfam ID: PF04430
• Sequence:
  MATALALRSLYRARPSLRCPPVELPWAPRRGHRLSPADDELYQRTRISLLQREAAQAMYI
  DSYNSRGFMINGNRVLGPCALLPHSVVQWNVGSHQDITEDSFSLFWLLEPRIEIVVVGTG
  DRTERLQSQVLQAMRQRGIAVEVQDTPNACATFNFLCHEGRVTGAALIPPPGGTSLTSLG
  QAAQ
• Function: Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[3]
Mitochondrial complex 1 deficiency, nuclear type 18	DIS8KP4P	Strong	Autosomal recessive	[4]
Leigh syndrome with cardiomyopathy	DIS2UELC	Supportive	Autosomal recessive	[3]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[4]

10 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 3 (NDUFAF3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH dehydrogenase 1 alpha subcomplex assembly factor 3 (NDUFAF3).	[13]

References

• [1] 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.
• [2] Identification of a novel estrogen receptor-alpha variant and its upstream splicing regulator.Mol Endocrinol. 2010 May;24(5):914-22. doi: 10.1210/me.2009-0413. Epub 2010 Mar 19.
• [3] Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome. Mol Genet Metab. 2017 Mar;120(3):243-246. doi: 10.1016/j.ymgme.2016.12.005. Epub 2016 Dec 11.
• [4] Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet. 2009 Jun;84(6):718-27. doi: 10.1016/j.ajhg.2009.04.020. Epub 2009 May 21.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [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] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] 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.