Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0UOKIT)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13)
• Synonyms: Cell death regulatory protein GRIM-19; Complex I-B16.6; CI-B16.6; Gene associated with retinoic and interferon-induced mortality 19 protein; GRIM-19; Gene associated with retinoic and IFN-induced mortality 19 protein; NADH-ubiquinone oxidoreductase B16.6 subunit
• Gene Name: NDUFA13
• Related Disease:
  Leigh syndrome
  Obsolete Leigh syndrome with leukodystrophy
  Mitochondrial complex 1 deficiency, nuclear type 28
  Thyroid Hurthle cell carcinoma
• UniProt ID: NDUAD_HUMAN
• PDB ID: 5XTB; 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF06212
• Sequence:
  MAASKVKQDMPPPGGYGPIDYKRNLPRRGLSGYSMLAIGIGTLIYGHWSIMKWNRERRRL
  QIEDFEARIALLPLLQAETDRRTLQMLRENLEEEAIIMKDVPDWKVGESVFHTTRWVPPL
  IGELYGLRTTEEALHASHGFMWYT
• 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. Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This apoptotic activity is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes. May play a role in CARD15-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes.
• Tissue Specificity: Widely expressed, with highest expression in heart, skeletal muscle, liver, kidney and placenta. In intestinal mucosa, down-regulated in areas involved in Crohn disease and ulcerative colitis.
• 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:HS05364-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[1]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[2]
Mitochondrial complex 1 deficiency, nuclear type 28	DIS2WTAE	Limited	Autosomal recessive	[3]
Thyroid Hurthle cell carcinoma	DISU2DYU	Limited	Unknown	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13) affects the response to substance of Paclitaxel.	[14]
Vinblastine	DM5TVS3	Approved	NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13) affects the response to substance of Vinblastine.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 13 (NDUFA13).	[13]

References

• [1] 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.
• [2] Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability. Hum Mol Genet. 2015 Jul 15;24(14):3948-55. doi: 10.1093/hmg/ddv133. Epub 2015 Apr 21.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] 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.
• [5] 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.
• [6] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [7] 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.
• [8] 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.
• [9] GRIM?19?mediated Stat3 activation is a determinant for resveratrol?induced proliferation and cytotoxicity in cervical tumor?derived cell lines. Mol Med Rep. 2015 Feb;11(2):1272-7. doi: 10.3892/mmr.2014.2797. Epub 2014 Oct 29.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [14] 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.