Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG2GU7J)

• DOT Name: Mitochondrial translation release factor in rescue (MTRFR)
• Gene Name: MTRFR
• Related Disease:
  Combined oxidative phosphorylation defect type 7
  Leigh syndrome
• UniProt ID: MTRFR_HUMAN
• PDB ID: 7A5H
• Pfam ID: PF00472
• Sequence:
  MSTVGLFHFPTPLTRICPAPWGLRLWEKLTLLSPGIAVTPVQMAGKKDYPALLSLDENEL
  EEQFVKGHGPGGQATNKTSNCVVLKHIPSGIVVKCHQTRSVDQNRKLARKILQEKVDVFY
  NGENSPVHKEKREAAKKKQERKKRAKETLEKKKLLKELWESSKKVH
• Function: Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation. As heterodimer with MTRES1, ejects the unfinished nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for MTRES1 and MTRF during mitoribosome rescue.
• Tissue Specificity: Expressed in all areas of the brain tested.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation defect type 7	DISZ2YBE	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial translation release factor in rescue (MTRFR).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondrial translation release factor in rescue (MTRFR).	[10]

References

• [1] Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. J Neuroophthalmol. 2014 Mar;34(1):39-43. doi: 10.1097/WNO.0000000000000076.
• [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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.