Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8QPRS)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2)
• Synonyms: B17.2-like; B17.2L; Mimitin; Myc-induced mitochondrial protein; MMTN; NDUFA12-like protein
• Gene Name: NDUFAF2
• Related Disease:
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 10
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: NDUF2_HUMAN
• Pfam ID: PF05071
• Sequence:
  MGWSQDLFRALWRSLSREVKEHVGTDQFGNKYYYIPQYKNWRGQTIREKRIVEAANKKEV
  DYEAGDIPTEWEAWIRRTRKTPPTMEEILKNEKHREEIKIKSQDFYEKEKLLSKETSEEL
  LPPPVQTQIKGHASAPYFGKEEPSVAPSSTGKTFQPGSWMPRDGKSHNQ
• Function: Acts as a molecular chaperone for mitochondrial complex I 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.
• Tissue Specificity: Highly expressed in ESCC cells. Also expressed in heart, skeletal muscle, liver, and in fibroblasts.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Mitochondrial complex 1 deficiency, nuclear type 10	DISDEDYH	Strong	Autosomal recessive	[2]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[3]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[5]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2).	[14]

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] The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Mol Genet Metab. 2008 May;94(1):78-82. doi: 10.1016/j.ymgme.2007.11.013. Epub 2008 Jan 3.
• [3] A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest. 2005 Oct;115(10):2784-92. doi: 10.1172/JCI26020.
• [4] High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [15] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.