Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMKQJJ8)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9)
• Synonyms: Complex I-39kD; CI-39kD; NADH-ubiquinone oxidoreductase 39 kDa subunit
• Gene Name: NDUFA9
• Related Disease:
  Alzheimer disease
  Dystonia
  Leigh syndrome
  Obsolete Leigh syndrome with leukodystrophy
  Axonal neuropathy
  Mitochondrial complex 1 deficiency, nuclear type 26
• UniProt ID: NDUA9_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF01370
• Sequence:
  MAAAAQSRVVRVLSMSRSAITAIATSVCHGPPCRQLHHALMPHGKGGRSSVSGIVATVFG
  ATGFLGRYVVNHLGRMGSQVIIPYRCDKYDIMHLRPMGDLGQLLFLEWDARDKDSIRRVV
  QHSNVVINLIGRDWETKNFDFEDVFVKIPQAIAQLSKEAGVEKFIHVSHLNANIKSSSRY
  LRNKAVGEKVVRDAFPEAIIVKPSDIFGREDRFLNSFASMHRFGPIPLGSLGWKTVKQPV
  YVVDVSKGIVNAVKDPDANGKSFAFVGPSRYLLFHLVKYIFAVAHRLFLPFPLPLFAYRW
  VARVFEISPFEPWITRDKVERMHITDMKLPHLPGLEDLGIQATPLELKAIEVLRRHRTYR
  WLSAEIEDVKPAKTVNI
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Required for proper complex I assembly. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
• 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:HS06589-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Dystonia	DISJLFGW	Strong	Genetic Variation	[2]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[3]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[4]
Axonal neuropathy	DIS5S2BC	Limited	Genetic Variation	[2]
Mitochondrial complex 1 deficiency, nuclear type 26	DISF1BMB	Limited	Autosomal recessive	[5]

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 dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[14]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
ME-344	DM6JN19	Phase 1/2	ME-344 increases the degradation of NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9).	[16]

References

• [1] Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer's disease.Mol Brain. 2019 Jan 28;12(1):8. doi: 10.1186/s13041-019-0430-y.
• [2] NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect.Clin Genet. 2018 Jan;93(1):111-118. doi: 10.1111/cge.13089. Epub 2017 Nov 21.
• [3] 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.
• [4] Defective NDUFA9 as a novel cause of neonatally fatal complex I disease. J Med Genet. 2012 Jan;49(1):10-5. doi: 10.1136/jmedgenet-2011-100466. Epub 2011 Nov 23.
• [5] Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome. J Med Genet. 2011 Nov;48(11):737-40. doi: 10.1136/jmg.2011.088856. Epub 2011 May 26.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [9] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [10] 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.
• [11] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer. Cell Death Dis. 2019 Nov 7;10(11):846. doi: 10.1038/s41419-019-2001-7.
• [14] 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.
• [15] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [16] Anti-cancer analogues ME-143 and ME-344 exert toxicity by directly inhibiting mitochondrial NADH: ubiquinone oxidoreductase (Complex I). Am J Cancer Res. 2015 Jan 15;5(2):689-701. eCollection 2015.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.