Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG47B7B)

• DOT Name: NADH-ubiquinone oxidoreductase chain 6 (ND6)
• Synonyms: EC 7.1.1.2; NADH dehydrogenase subunit 6
• Gene Name: ND6
• Related Disease:
  Leber hereditary optic neuropathy
  Anxiety
  Epilepsy
  Fatty liver disease
  Hereditary optic atrophy
  Klinefelter syndrome
  Leber plus disease
  Lung adenocarcinoma
  Maternally-inherited Leigh syndrome
  Metastatic malignant neoplasm
  Non-alcoholic fatty liver disease
  Optic nerve disorder
  Pathologic nystagmus
  Prostate cancer
  Prostate carcinoma
  Anxiety disorder
  Blindness
  Dystonia
  Fetal growth restriction
  Leigh syndrome
  MELAS syndrome
  Nervous system disease
• UniProt ID: NU6M_HUMAN
• PDB ID: 5XTC; 5XTD
• EC Number: 7.1.1.2
• Pfam ID: PF00499
• Sequence:
  MMYALFLLSVGLVMGFVGFSSKPSPIYGGLVLIVSGVVGCVIILNFGGGYMGLMVFLIYL
  GGMMVVFGYTTAMAIEEYPEAWGSGVEVLVSVLVGLAMEVGLVLWVKEYDGVVVVVNFNS
  VGSWMIYEGEGSGLIREDPIGAGALYDYGRWLVVVTGWTLFVGVYIVIEIARGN
• 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:HS00036-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
Leber hereditary optic neuropathy	DIS7Y2EE	Definitive	Genetic Variation	[1]
Anxiety	DISIJDBA	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[4]
Hereditary optic atrophy	DISCV4E4	Strong	Biomarker	[5]
Klinefelter syndrome	DISOUI7W	Strong	Altered Expression	[6]
Leber plus disease	DISTRG53	Strong	GermlineCausalMutation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Maternally-inherited Leigh syndrome	DISGE06V	Strong	GermlineCausalMutation	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[10]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[4]
Optic nerve disorder	DISSOQM8	Strong	Genetic Variation	[11]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[2]
Blindness	DISTIM10	Limited	Genetic Variation	[14]
Dystonia	DISJLFGW	Limited	Genetic Variation	[15]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[16]
Leigh syndrome	DISWQU45	Limited	Genetic Variation	[1]
MELAS syndrome	DIS81Z3S	Limited	Genetic Variation	[17]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	NADH-ubiquinone oxidoreductase chain 6 (ND6) decreases the response to substance of Doxorubicin.	[26]

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 6 (ND6).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[21]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of NADH-ubiquinone oxidoreductase chain 6 (ND6).	[25]

References

• [1] Personalized pediatric ophthalmology: a case report.J AAPOS. 2019 Aug;23(4):234-236. doi: 10.1016/j.jaapos.2019.03.003. Epub 2019 May 23.
• [2] 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.
• [3] Juvenile Leigh syndrome, optic atrophy, ataxia, dystonia, and epilepsy due to T14487C mutation in the mtDNA-ND6 gene: a mitochondrial syndrome presenting from birth to adolescence.J Child Neurol. 2011 Apr;26(4):476-81. doi: 10.1177/0883073810384615. Epub 2010 Dec 31.
• [4] Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease.Gut. 2013 Sep;62(9):1356-63. doi: 10.1136/gutjnl-2012-302962. Epub 2012 Aug 9.
• [5] Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy.Ann Neurol. 1999 Mar;45(3):320-8.
• [6] Next Generation Sequencing expression profiling of mitochondrial subunits in men with Klinefelter syndrome.Int J Med Sci. 2018 Jan 1;15(1):31-35. doi: 10.7150/ijms.21075. eCollection 2018.
• [7] Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia.Am J Hum Genet. 1996 Apr;58(4):703-11.
• [8] Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma.BMC Cancer. 2015 May 2;15:346. doi: 10.1186/s12885-015-1349-z.
• [9] Severe infantile leigh syndrome associated with a rare mitochondrial ND6 mutation, m.14487T>C.Am J Med Genet A. 2013 Aug;161A(8):2020-3. doi: 10.1002/ajmg.a.36000. Epub 2013 Jun 27.
• [10] Regulation of metastasis; mitochondrial DNA mutations have appeared on stage.J Bioenerg Biomembr. 2012 Dec;44(6):639-44. doi: 10.1007/s10863-012-9468-6.
• [11] The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy.Brain. 2001 Jan;124(Pt 1):209-18. doi: 10.1093/brain/124.1.209.
• [12] Genetic aetiology of ophthalmological manifestations in children - a focus on mitochondrial disease-related symptoms.Acta Ophthalmol. 2016 Feb;94(1):83-91. doi: 10.1111/aos.12897. Epub 2015 Oct 8.
• [13] Somatic mutations throughout the entire mitochondrial genome are associated with elevated PSA levels in prostate cancer patients.Am J Hum Genet. 2010 Dec 10;87(6):802-12. doi: 10.1016/j.ajhg.2010.11.001.
• [14] Mitochondrial DNA sequence variation in human evolution and disease.Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8739-46. doi: 10.1073/pnas.91.19.8739.
• [15] Molecular diagnostic experience of whole-exome sequencing in adult patients.Genet Med. 2016 Jul;18(7):678-85. doi: 10.1038/gim.2015.142. Epub 2015 Dec 3.
• [16] Mitochondrial and glycolysis-regulatory gene expression profiles are associated with intrauterine growth restriction.J Matern Fetal Neonatal Med. 2020 Apr;33(8):1336-1345. doi: 10.1080/14767058.2018.1518419. Epub 2018 Sep 25.
• [17] An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.Eur J Hum Genet. 2001 Oct;9(10):805-9. doi: 10.1038/sj.ejhg.5200712.
• [18] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] 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.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [26] Mutation in mitochondrial complex I ND6 subunit is associated with defective response to hypoxia in human glioma cells. Mol Cancer. 2004 Jul 12;3:19. doi: 10.1186/1476-4598-3-19.