Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9EVJYG)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8)
• Gene Name: NDUFAF8
• Related Disease:
  Frontotemporal dementia
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 34
  Mitochondrial complex I deficiency
• UniProt ID: NDUF8_HUMAN
• Sequence:
  MSANGAVWGRVRSRLRAFPERLAACGAEAAAYGRCVQASTAPGGRLSKDFCAREFEALRS
  CFAAAAKKTLEGGC
• Function: Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1). Required to stabilize NDUFAF5.
• KEGG Pathway: Thermogenesis (hsa04714)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[1]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[2]
Mitochondrial complex 1 deficiency, nuclear type 34	DISKZUVS	Moderate	Autosomal recessive	[3]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[4]

2 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 assembly factor 8 (NDUFAF8).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of NADH dehydrogenase 1 alpha subcomplex assembly factor 8 (NDUFAF8).	[11]

References

• [1] A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.Neurobiol Aging. 2015 Oct;36(10):2904.e13-26. doi: 10.1016/j.neurobiolaging.2015.06.005. Epub 2015 Jun 12.
• [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] 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] Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency. Am J Hum Genet. 2020 Jan 2;106(1):92-101. doi: 10.1016/j.ajhg.2019.12.001. Epub 2019 Dec 19.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.