Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6)
• Synonyms: Complex I-B14; CI-B14; LYR motif-containing protein 6; NADH-ubiquinone oxidoreductase B14 subunit
• Gene Name: NDUFA6
• Related Disease:
  Alzheimer disease
  Bipolar disorder
  HIV infectious disease
  Mitochondrial complex 1 deficiency, nuclear type 33
  Mitochondrial complex I deficiency
• UniProt ID: NDUA6_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF13233
• Sequence:
  MAGSGVRQATSTASTFVKPIFSRDMNEAKRRVRELYRAWYREVPNTVHQFQLDITVKMGR
  DKVREMFMKNAHVTDPRVVDLLVIKGKIELEETIKVWKQRTHVMRFFHETEAPRPKDFLS
  KFYVGHDP
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Required for proper 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.
• 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:HS00037-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[3]
Mitochondrial complex 1 deficiency, nuclear type 33	DIS0K7HY	Strong	Autosomal recessive	[4]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 6 (NDUFA6).	[13]

References

• [1] Association of gene expression and methylation of UQCRC1 to the predisposition of Alzheimer's disease in a Chinese population.J Psychiatr Res. 2016 May;76:143-7. doi: 10.1016/j.jpsychires.2016.02.010. Epub 2016 Feb 18.
• [2] Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.Eur Neuropsychopharmacol. 2015 Apr;25(4):468-73. doi: 10.1016/j.euroneuro.2015.02.002. Epub 2015 Feb 16.
• [3] Mitochondrial complex I activity is impaired during HIV-1-induced T-cell apoptosis.Cell Death Differ. 2005 Nov;12(11):1417-28. doi: 10.1038/sj.cdd.4401668.
• [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] Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency. Am J Hum Genet. 2018 Oct 4;103(4):592-601. doi: 10.1016/j.ajhg.2018.08.013. Epub 2018 Sep 20.
• [6] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [7] 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.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.