Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9OHOX)

• DOT Name: NADH-ubiquinone oxidoreductase chain 2 (ND2)
• Synonyms: EC 7.1.1.2; NADH dehydrogenase subunit 2
• Gene Name: ND2
• Related Disease:
  Cerebrovascular disease
  Myocardial infarction
  Myocardial ischemia
  OPTN-related open angle glaucoma
  Age-related macular degeneration
  Alzheimer disease
  Colorectal carcinoma
  Essential hypertension
  High blood pressure
  Leber hereditary optic neuropathy
  Leigh syndrome
  Maternally-inherited Leigh syndrome
  Mitochondrial complex I deficiency
  Multiple sclerosis
  Pancreatic cancer
  Parkinson disease
  Peripheral neuropathy
  Squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Anxiety
  Anxiety disorder
• UniProt ID: NU2M_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF06444 ; PF00361
• Sequence:
  MNPLAQPVIYSTIFAGTLITALSSHWFFTWVGLEMNMLAFIPVLTKKMNPRSTEAAIKYF
  LTQATASMILLMAILFNNMLSGQWTMTNTTNQYSSLMIMMAMAMKLGMAPFHFWVPEVTQ
  GTPLTSGLLLLTWQKLAPISIMYQISPSLNVSLLLTLSILSIMAGSWGGLNQTQLRKILA
  YSSITHMGWMMAVLPYNPNMTILNLTIYIILTTTAFLLLNLNSSTTTLLLSRTWNKLTWL
  TPLIPSTLLSLGGLPPLTGFLPKWAIIEEFTKNNSLIIPTIMATITLLNLYFYLRLIYST
  SITLLPMSNNVKMKWQFEHTKPTPFLPTLIALTTLLLPISPFMLMIL
• 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 and assembly 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:HS17772-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebrovascular disease	DISAB237	Definitive	Genetic Variation	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[2]
Myocardial ischemia	DISFTVXF	Definitive	Genetic Variation	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[3]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[6]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[8]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[9]
Maternally-inherited Leigh syndrome	DISGE06V	Strong	GermlineCausalMutation	[9]
Mitochondrial complex I deficiency	DIS13M7V	Strong	GermlineCausalMutation	[10]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[11]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[12]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[13]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[15]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[16]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[16]
Anxiety	DISIJDBA	Limited	Biomarker	[17]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[17]

12 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 2 (ND2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[22]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[26]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[27]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[28]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of NADH-ubiquinone oxidoreductase chain 2 (ND2).	[29]

References

• [1] Interaction between longevity-associated mitochondrial DNA 5178 C/A polymorphism and cigarette smoking on hematological parameters in Japanese men.Arch Gerontol Geriatr. 2005 Mar-Apr;40(2):113-22. doi: 10.1016/j.archger.2004.07.003.
• [2] Association of a 5178C-->A (Leu237Met) polymorphism in the mitochondrial DNA with a low prevalence of myocardial infarction in Japanese individuals.Atherosclerosis. 2004 Aug;175(2):281-6. doi: 10.1016/j.atherosclerosis.2004.03.008.
• [3] Mitochondrial DNA Variation and Disease Susceptibility in Primary Open-Angle Glaucoma.Invest Ophthalmol Vis Sci. 2018 Sep 4;59(11):4598-4602. doi: 10.1167/iovs.18-25085.
• [4] Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):4027-4038. doi: 10.1167/iovs.17-21734.
• [5] Investigations on the point mutations at nt 5460 of the mtDNA in different neurodegenerative and neuromuscular diseases.Eur Neurol. 1996;36(3):149-53. doi: 10.1159/000117233.
• [6] Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.PLoS One. 2015 Sep 4;10(9):e0136796. doi: 10.1371/journal.pone.0136796. eCollection 2015.
• [7] Interaction between mitochondrial NADH dehydrogenase subunit-2 5178 C > A and clinical risk factors on the susceptibility of essential hypertension in Chinese population.BMC Med Genet. 2019 Jul 5;20(1):121. doi: 10.1186/s12881-019-0838-3.
• [8] Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.Genetics. 1992 Jan;130(1):163-73. doi: 10.1093/genetics/130.1.163.
• [9] Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome.Mol Genet Metab. 2007 Jan;90(1):10-4. doi: 10.1016/j.ymgme.2006.08.003. Epub 2006 Sep 22.
• [10] Nonsense mutations in mitochondrial DNA associated with myalgia and exercise intolerance.Neurology. 2005 Mar 22;64(6):1091-2. doi: 10.1212/01.WNL.0000154471.33156.55.
• [11] Mitochondrial DNA T4216C and A4917G variations in multiple sclerosis.J Neurol Sci. 2015 Sep 15;356(1-2):55-60. doi: 10.1016/j.jns.2015.04.050. Epub 2015 May 7.
• [12] Mitochondrial DNA sequence variation and risk of pancreatic cancer.Cancer Res. 2012 Feb 1;72(3):686-95. doi: 10.1158/0008-5472.CAN-11-1682. Epub 2011 Dec 15.
• [13] Association of the mt-ND2 5178A/C polymorphism with Parkinson's disease.Neurosci Lett. 2015 Feb 5;587:98-101. doi: 10.1016/j.neulet.2014.12.005. Epub 2014 Dec 12.
• [14] The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy.Pharmacogenomics J. 2008 Feb;8(1):71-7. doi: 10.1038/sj.tpj.6500470. Epub 2007 Aug 7.
• [15] Mitochondrial DNA mutations in oral squamous cell carcinoma.Carcinogenesis. 2006 May;27(5):945-50. doi: 10.1093/carcin/bgi326. Epub 2006 Jan 10.
• [16] Association between mitochondrial genetic variation and breast cancer risk: The Multiethnic Cohort.PLoS One. 2019 Oct 2;14(10):e0222284. doi: 10.1371/journal.pone.0222284. eCollection 2019.
• [17] Mitochondrial Gene Expression Profiles Are Associated with Maternal Psychosocial Stress in Pregnancy and Infant Temperament.PLoS One. 2015 Sep 29;10(9):e0138929. doi: 10.1371/journal.pone.0138929. eCollection 2015.
• [18] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] 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.
• [26] In vitro blood brain barrier exposure to mycotoxins and carotenoids pumpkin extract alters mitochondrial gene expression and oxidative stress. Food Chem Toxicol. 2021 Jul;153:112261. doi: 10.1016/j.fct.2021.112261. Epub 2021 May 17.
• [27] 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.
• [28] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [29] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.