Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1OC3K3)

• DOT Name: NADH-ubiquinone oxidoreductase chain 3 (ND3)
• Synonyms: EC 7.1.1.2; NADH dehydrogenase subunit 3
• Gene Name: ND3
• Related Disease:
  Mitochondrial complex I deficiency
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Dystonia
  Fatty liver disease
  Huntington disease
  Hypothyroidism
  MELAS syndrome
  Mitochondrial disease
  Neoplasm
  Parkinson disease
  Renal cell carcinoma
  Leber plus disease
  Gastric cancer
  Leigh syndrome
  Maternally-inherited Leigh syndrome
  Stomach cancer
• UniProt ID: NU3M_HUMAN
• PDB ID: 5XTC; 5XTD
• EC Number: 7.1.1.2
• Pfam ID: PF00507
• Sequence:
  MNFALILMINTLLALLLMIITFWLPQLNGYMEKSTPYECGFDPMSPARVPFSMKFFLVAI
  TFLLFDLEIALLLPLPWALQTTNLPLMVMSSLLLIIILALSLAYEWLQKGLDWTE
• Function: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity of complex I.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  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:HS00032-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex I deficiency	DIS13M7V	Definitive	GermlineCausalMutation	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Dystonia	DISJLFGW	Strong	Genetic Variation	[4]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[5]
Huntington disease	DISQPLA4	Strong	Biomarker	[6]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[7]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[8]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Leber plus disease	DISTRG53	Disputed	GermlineCausalMutation	[11]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[12]
Leigh syndrome	DISWQU45	Limited	Genetic Variation	[8]
Maternally-inherited Leigh syndrome	DISGE06V	Limited	GermlineCausalMutation	[13]
Stomach cancer	DISKIJSX	Limited	Genetic Variation	[12]

9 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-ubiquinone oxidoreductase chain 3 (ND3).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[18]
Fialuridine	DMCIGRB	Phase 2	Fialuridine decreases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of NADH-ubiquinone oxidoreductase chain 3 (ND3).	[22]

References

• [1] De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol. 2004 Jan;55(1):58-64. doi: 10.1002/ana.10787.
• [2] Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes.Ann Diagn Pathol. 2018 Feb;32:23-27. doi: 10.1016/j.anndiagpath.2017.09.001. Epub 2017 Sep 10.
• [3] Detection of mitochondrial genome depletion by a novel cDNA in renal cell carcinoma.Lab Invest. 1996 Mar;74(3):592-9.
• [4] A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia.Am J Med Genet A. 2007 Jan 1;143A(1):33-41. doi: 10.1002/ajmg.a.31565.
• [5] Highly expressed MT-ND3 positively associated with histological severity of hepatic steatosis.APMIS. 2014 May;122(5):443-51. doi: 10.1111/apm.12166. Epub 2013 Sep 11.
• [6] Nitric oxide mechanism in the protective effect of antidepressants against 3-nitropropionic acid-induced cognitive deficit, glutathione and mitochondrial alterations in animal model of Huntington's disease.Behav Pharmacol. 2010 May;21(3):217-30. doi: 10.1097/fbp.0b013e32833a5bf4.
• [7] Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis.Biochem Biophys Res Commun. 1995 May 25;210(3):995-1000. doi: 10.1006/bbrc.1995.1755.
• [8] Transition from Leigh syndrome to MELAS syndrome in a patient with heteroplasmic MT-ND3 m.10158T>C.Brain Dev. 2019 Oct;41(9):803-807. doi: 10.1016/j.braindev.2019.05.006. Epub 2019 Jun 6.
• [9] Complex I deficiency related to T10158C mutation ND3 gene: A further definition of the clinical spectrum.Brain Dev. 2017 Mar;39(3):261-265. doi: 10.1016/j.braindev.2016.09.013. Epub 2016 Oct 11.
• [10] Protective effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson's disease.Neurochem Res. 2011 Aug;36(8):1435-43. doi: 10.1007/s11064-011-0469-3. Epub 2011 Apr 12.
• [11] Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics. 2009 Oct;10(4):337-45. doi: 10.1007/s10048-009-0194-0. Epub 2009 May 21.
• [12] Mitochondrial NADH Dehydrogenase Subunit 3 (MTND3) Polymorphisms are Associated with Gastric Cancer Susceptibility.Int J Med Sci. 2018 Aug 10;15(12):1329-1333. doi: 10.7150/ijms.26881. eCollection 2018.
• [13] The clinical spectrum of the m.10191T>C mutation in complex I-deficient Leigh syndrome.Dev Med Child Neurol. 2012 Jun;54(6):500-6. doi: 10.1111/j.1469-8749.2012.04224.x. Epub 2012 Feb 27.
• [14] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [19] Mechanisms of Chronic Fialuridine Hepatotoxicity as Revealed in Primary Human Hepatocyte Spheroids. Toxicol Sci. 2019 Oct 1;171(2):385-395. doi: 10.1093/toxsci/kfz195.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [22] 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.