Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4RQVAA)

• DOT Name: NADH-ubiquinone oxidoreductase chain 4 (ND4)
• Synonyms: EC 7.1.1.2; NADH dehydrogenase subunit 4
• Gene Name: ND4
• Related Disease:
  Acute myelogenous leukaemia
  Intellectual disability
  Alzheimer disease
  B-cell neoplasm
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Cerebellar ataxia
  Cystic fibrosis
  Deafness
  Esophageal cancer
  Head and neck cancer
  Head and neck carcinoma
  Hereditary optic atrophy
  Leber plus disease
  Leigh syndrome
  Major depressive disorder
  Maternally-inherited Leigh syndrome
  MELAS syndrome
  Mitochondrial myopathy
  Neoplasm of esophagus
  Schizophrenia
  Ulcerative colitis
  Uveitis
  Lactic acidosis
  Leber congenital amaurosis
  Leber hereditary optic neuropathy
  Ocular infection
  Cardiomyopathy
  Optic nerve disorder
  Psychotic disorder
  Spinocerebellar ataxia type 3
• UniProt ID: NU4M_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF01059 ; PF00361
• Sequence:
  MLKLIVPTIMLLPLTWLSKKHMIWINTTTHSLIISIIPLLFFNQINNNLFSCSPTFSSDP
  LTTPLLMLTTWLLPLTIMASQRHLSSEPLSRKKLYLSMLISLQISLIMTFTATELIMFYI
  FFETTLIPTLAIITRWGNQPERLNAGTYFLFYTLVGSLPLLIALIYTHNTLGSLNILLLT
  LTAQELSNSWANNLMWLAYTMAFMVKMPLYGLHLWLPKAHVEAPIAGSMVLAAVLLKLGG
  YGMMRLTLILNPLTKHMAYPFLVLSLWGMIMTSSICLRQTDLKSLIAYSSISHMALVVTA
  ILIQTPWSFTGAVILMIAHGLTSSLLFCLANSNYERTHSRIMILSQGLQTLLPLMAFWWL
  LASLANLALPPTINLLGELSVLVTTFSWSNITLLLTGLNMLVTALYSLYMFTTTQWGSLT
  HHINNMKPSFTRENTLMFMHLSPILLLSLNPDIITGFSS
• 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:HS00033-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[8]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[9]
Deafness	DISKCLH4	Strong	Genetic Variation	[10]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[7]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[11]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[11]
Hereditary optic atrophy	DISCV4E4	Strong	Biomarker	[12]
Leber plus disease	DISTRG53	Strong	GermlineCausalMutation	[13]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[14]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Maternally-inherited Leigh syndrome	DISGE06V	Strong	GermlineCausalMutation	[15]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[16]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[17]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[18]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[19]
Uveitis	DISV0RYS	Strong	Biomarker	[20]
Lactic acidosis	DISZI1ZK	moderate	Genetic Variation	[21]
Leber congenital amaurosis	DISMGH8F	moderate	Genetic Variation	[22]
Leber hereditary optic neuropathy	DIS7Y2EE	moderate	Biomarker	[23]
Ocular infection	DISTTJES	moderate	Genetic Variation	[24]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[25]
Optic nerve disorder	DISSOQM8	Limited	Genetic Variation	[26]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[27]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Altered Expression	[28]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
CERC-801	DM3SZ7P	Phase 2	NADH-ubiquinone oxidoreductase chain 4 (ND4) affects the metabolism of CERC-801.	[45]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[31]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[33]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[34]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[35]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[36]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[37]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[39]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[41]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[42]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[43]
Ethidium	DMMEQUR	Investigative	Ethidium decreases the expression of NADH-ubiquinone oxidoreductase chain 4 (ND4).	[44]

References

• [1] Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia.Leukemia. 2012 Feb;26(2):289-95. doi: 10.1038/leu.2011.200. Epub 2011 Aug 9.
• [2] Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability.Hum Mol Genet. 2018 Mar 1;27(5):891-900. doi: 10.1093/hmg/ddy009.
• [3] SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease.Aging Cell. 2018 Feb;17(1):e12679. doi: 10.1111/acel.12679. Epub 2017 Nov 11.
• [4] Comparative analysis of testis transcriptomes associated with male infertility in triploid cyprinid fish.Reprod Fertil Dev. 2019 Jan;31(2):248-260. doi: 10.1071/RD18034.
• [5] Mitochondrial DNA (mtDNA) in brain samples from patients with major psychiatric disorders: gene expression profiles, mtDNA content and presence of the mtDNA common deletion.Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):213-23. doi: 10.1002/ajmg.b.32134. Epub 2013 Jan 25.
• [6] The variation of mitochondrial NADH dehydrogenase subunit 4 (mtND4) and molecular dynamics simulation of SNPs among Iranian women with breast cancer.J Mol Graph Model. 2018 Oct;85:242-249. doi: 10.1016/j.jmgm.2018.08.011. Epub 2018 Sep 4.
• [7] High incidence of coding gene mutations in mitochondrial DNA in esophageal cancer.Mol Med Rep. 2017 Dec;16(6):8537-8541. doi: 10.3892/mmr.2017.7663. Epub 2017 Sep 29.
• [8] Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light.Hum Mutat. 2019 Dec;40(12):2430-2443. doi: 10.1002/humu.23885. Epub 2019 Aug 26.
• [9] The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis.Biochem Biophys Res Commun. 2007 May 11;356(3):805-9. doi: 10.1016/j.bbrc.2007.03.057. Epub 2007 Mar 19.
• [10] The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family.Biochem Biophys Res Commun. 2007 Oct 26;362(3):670-6. doi: 10.1016/j.bbrc.2007.08.034. Epub 2007 Aug 15.
• [11] Mutations and polymorphisms in mitochondrial DNA in head and neck cancer cell lines.Acta Otorhinolaryngol Ital. 2006 Aug;26(4):185-90.
• [12] Mitochondrial genetic control of assembly and function of complex I in mammalian cells.J Bioenerg Biomembr. 2001 Jun;33(3):251-7. doi: 10.1023/a:1010791204961.
• [13] 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.
• [14] Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome.J Hum Genet. 2017 Feb;62(2):291-297. doi: 10.1038/jhg.2016.127. Epub 2016 Oct 20.
• [15] Mitochondrial DNA 11777C>A mutation associated Leigh syndrome: case report with a review of the previously described pedigrees.Neuromolecular Med. 2010 Sep;12(3):277-84. doi: 10.1007/s12017-010-8115-9. Epub 2010 May 26.
• [16] A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I.Am J Hum Genet. 1992 Sep;51(3):457-68.
• [17] Mitochondrial DNA deletions in inclusion body myositis.Brain. 1993 Apr;116 ( Pt 2):325-36. doi: 10.1093/brain/116.2.325.
• [18] A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress.Schizophr Res. 2003 Dec 1;65(1):33-8. doi: 10.1016/s0920-9964(03)00011-2.
• [19] Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study.BMC Gastroenterol. 2016 Oct 3;16(1):118. doi: 10.1186/s12876-016-0509-1.
• [20] Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial.JAMA Ophthalmol. 2019 Apr 1;137(4):399-406. doi: 10.1001/jamaophthalmol.2018.6902.
• [21] The expanding clinical spectrum of mitochondrial diseases.Brain Dev. 1993 Jan-Feb;15(1):1-22. doi: 10.1016/0387-7604(93)90002-p.
• [22] Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease.Invest Ophthalmol Vis Sci. 1993 Mar;34(3):488-95.
• [23] Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.Clin Exp Ophthalmol. 2019 Aug;47(6):774-778. doi: 10.1111/ceo.13515. Epub 2019 May 8.
• [24] Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial.JAMA Ophthalmol. 2014 Apr 1;132(4):409-20. doi: 10.1001/jamaophthalmol.2013.7630.
• [25] A double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber's hereditary optic neuropathy and cardiomyopathy.J Hum Genet. 2003;48(1):47-50. doi: 10.1007/s100380300005.
• [26] An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene.Am J Hum Genet. 1990 Oct;47(4):629-34.
• [27] Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder.J Psychiatr Res. 2017 Jan;84:221-226. doi: 10.1016/j.jpsychires.2016.09.027. Epub 2016 Sep 30.
• [28] Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease.Mol Neurobiol. 2019 Jan;56(1):119-124. doi: 10.1007/s12035-018-1069-x. Epub 2018 Apr 21.
• [29] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [30] 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.
• [31] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [32] Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers. Am J Pathol. 2011 May;178(5):2066-76.
• [33] [Construction of subtracted cDNA library in human Jurkat T cell line induced by arsenic trioxide in vitro]. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 Nov;37(6):403-7.
• [34] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [35] Etoposide induces necrosis through p53-mediated antiapoptosis in human kidney proximal tubule cells. Toxicol Sci. 2015 Nov;148(1):204-19.
• [36] 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.
• [37] Inhibition of mitochondrial function in HL60 cells is associated with an increased apoptosis and expression of CD14. Biochem Biophys Res Commun. 1999 Sep 24;263(2):294-300. doi: 10.1006/bbrc.1999.1356.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [40] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [41] 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.
• [42] 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.
• [43] 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.
• [44] The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts. Toxicol Appl Pharmacol. 2012 May 15;261(1):42-9. doi: 10.1016/j.taap.2012.03.009.
• [45] Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy. J Biol Chem. 1996 May 31;271(22):13155-61. doi: 10.1074/jbc.271.22.13155.