Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYK9JU6)

• DOT Name: Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1)
• Synonyms: NADH dehydrogenase 1 alpha subcomplex assembly factor 1
• Gene Name: NDUFAF1
• Related Disease:
  Mitochondrial disease
  Mitochondrial complex I deficiency
  Hypertrophic cardiomyopathy
  Mitochondrial complex 1 deficiency, nuclear type 11
• UniProt ID: CIA30_HUMAN
• Pfam ID: PF08547
• Sequence:
  MALVHKLLRGTYFLRKFSKPTSALYPFLGIRFAEYSSSLQKPVASPGKASSQRKTEGDLQ
  GDHQKEVALDITSSEEKPDVSFDKAIRDEAIYHFRLLKDEIVDHWRGPEGHPLHEVLLEQ
  AKVVWQFRGKEDLDKWTVTSDKTIGGRSEVFLKMGKNNQSALLYGTLSSEAPQDGESTRS
  GYCAMISRIPRGAFERKMSYDWSQFNTLYLRVRGDGRPWMVNIKEDTDFFQRTNQMYSYF
  MFTRGGPYWQEVKIPFSKFFFSNRGRIRDVQHELPLDKISSIGFTLADKVDGPFFLEIDF
  IGVFTDPAHTEEFAYENSPELNPRLFK
• Function: As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
• Tissue Specificity: Ubiquitous.
• 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
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[1]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[3]
Mitochondrial complex 1 deficiency, nuclear type 11	DISUCV9F	Limited	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[14]

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 decreases the methylation of Complex I intermediate-associated protein 30, mitochondrial (NDUFAF1).	[11]

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] Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J. 2007 Jul 11;26(13):3227-37. doi: 10.1038/sj.emboj.7601748. Epub 2007 Jun 7.
• [3] Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy.J Med Genet. 2011 Oct;48(10):691-7. doi: 10.1136/jmedgenet-2011-100340.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.