Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSZF7D6)

• DOT Name: NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2)
• Synonyms: NDUFV2; EC 7.1.1.2; NADH-ubiquinone oxidoreductase 24 kDa subunit
• Gene Name: NDUFV2
• Related Disease:
  Idiopathic cardiomyopathy
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Autosomal dominant optic atrophy, classic form
  Bipolar depression
  Bipolar disorder
  Bipolar I disorder
  Cardiomyopathy
  Mitochondrial complex 1 deficiency, nuclear type 7
  Neuroblastoma
  Schizophrenia
  Mitochondrial complex I deficiency
  Obsolete Leigh syndrome with leukodystrophy
  Leigh syndrome
• UniProt ID: NDUV2_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• EC Number: 7.1.1.2
• Pfam ID: PF01257
• Sequence:
  MFFSAALRARAAGLTAHWGRHVRNLHKTVMQNGAGGALFVHRDTPENNPDTPFDFTPENY
  KRIEAIVKNYPEGHKAAAVLPVLDLAQRQNGWLPISAMNKVAEVLQVPPMRVYEVATFYT
  MYNRKPVGKYHIQVCTTTPCMLRNSDSILEAIQKKLGIKVGETTPDKLFTLIEVECLGAC
  VNAPMVQINDNYYEDLTAKDIEEIIDELKAGKIPKPGPRSGRFSCEPAGGLTSLTEPPKG
  PGFGVQAGL
• 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 (Probable). Parts of the peripheral arm of the enzyme, where the electrons from NADH are accepted by flavin mononucleotide (FMN) and then passed along a chain of iron-sulfur clusters by electron tunnelling to the final acceptor ubiquinone (Probable). Contains one iron-sulfur cluster (Probable).
• 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:HS11253-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Idiopathic cardiomyopathy	DISUGBZL	Definitive	Biomarker	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Mitochondrial encephalomyopathy	DISA6PTN	Definitive	Biomarker	[1]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[3]
Bipolar depression	DISA75FU	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Bipolar I disorder	DISD09EH	Strong	Altered Expression	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[1]
Mitochondrial complex 1 deficiency, nuclear type 7	DISCD76Q	Strong	Autosomal recessive	[6]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[6]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[9]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2) affects the response to substance of Vinblastine.	[21]

3 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 dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2).	[19]

References

• [1] Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet. 2004 Jan;41(1):14-7. doi: 10.1136/jmg.2003.014316.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Fluoride-induced renal dysfunction via respiratory chain complex abnormal expression and fusion elevation in mice.Chemosphere. 2020 Jan;238:124607. doi: 10.1016/j.chemosphere.2019.124607. Epub 2019 Aug 17.
• [4] Expression of mitochondrial complex I subunit gene NDUFV2 in the lymphoblastoid cells derived from patients with bipolar disorder and schizophrenia.Neurosci Res. 2009 Mar;63(3):199-204. doi: 10.1016/j.neures.2008.12.004. Epub 2008 Dec 24.
• [5] Mitochondrial complex I and III mRNA levels in bipolar disorder.J Affect Disord. 2015 Sep 15;184:160-3. doi: 10.1016/j.jad.2015.05.060. Epub 2015 Jun 10.
• [6] Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Hum Mutat. 2003 Jun;21(6):582-6. doi: 10.1002/humu.10225.
• [7] Sp1 expression is disrupted in schizophrenia; a possible mechanism for the abnormal expression of mitochondrial complex I genes, NDUFV1 and NDUFV2.PLoS One. 2007 Sep 5;2(9):e817. doi: 10.1371/journal.pone.0000817.
• [8] NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia.Mol Psychiatry. 2020 Apr;25(4):805-820. doi: 10.1038/s41380-018-0309-9. Epub 2018 Dec 10.
• [9] Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. Eur J Paediatr Neurol. 2015 Sep;19(5):525-32. doi: 10.1016/j.ejpn.2015.05.002. Epub 2015 May 14.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet. 2014 Apr 15;23(8):2106-19.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.