Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCD6I5M)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12)
• Synonyms: 13 kDa differentiation-associated protein; Complex I-B17.2; CI-B17.2; CIB17.2; NADH-ubiquinone oxidoreductase subunit B17.2
• Gene Name: NDUFA12
• Related Disease:
  Mitochondrial complex 1 deficiency, nuclear type 23
  Alzheimer disease
  Coronary heart disease
  Obsolete Leigh syndrome with leukodystrophy
  Leigh syndrome
  Non-insulin dependent diabetes
• UniProt ID: NDUAC_HUMAN
• PDB ID: 5XTB; 5XTD; 5XTH; 5XTI
• Pfam ID: PF05071
• Sequence:
  MELVQVLKRGLQQITGHGGLRGYLRVFFRTNDAKVGTLVGEDKYGNKYYEDNKQFFGRHR
  WVVYTTEMNGKNTFWDVDGSMVPPEWHRWLHSMTDDPPTTKPLTARKFIWTNHKFNVTGT
  PEQYVPYSTTRKKIQEWIPPSTPYK
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. 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:HS03370-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
Mitochondrial complex 1 deficiency, nuclear type 23	DISRMDH5	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[3]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[4]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of NADH dehydrogenase 1 alpha subcomplex subunit 12 (NDUFA12).	[15]

References

• [1] 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.
• [2] Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies.PLoS One. 2014 Apr 22;9(4):e95413. doi: 10.1371/journal.pone.0095413. eCollection 2014.
• [3] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [4] 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.
• [5] The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus.Physiol Res. 2017 Nov 24;66(5):811-822. doi: 10.33549/physiolres.933469. Epub 2017 Jul 18.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] 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.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.