Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBIRR8Q)

• DOT Name: Mitochondrial Rho GTPase 1 (RHOT1)
• Synonyms: MIRO-1; hMiro-1; EC 3.6.5.-; Rac-GTP-binding protein-like protein; Ras homolog gene family member T1
• Gene Name: RHOT1
• Related Disease:
  Epilepsy
  Late-onset Parkinson disease
  Neuroblastoma
  Parkinson disease
  Status epilepticus seizure
  Amyotrophic lateral sclerosis
  Hyperglycemia
  Non-insulin dependent diabetes
  Pulmonary disease
  Stroke
  Type-1/2 diabetes
• UniProt ID: MIRO1_HUMAN
• PDB ID: 5KSO; 5KSP; 5KSY; 5KSZ; 5KTY; 5KU1; 6D71
• EC Number: 3.6.5.-
• Pfam ID: PF08355 ; PF08356 ; PF00071
• Sequence:
  MKKDVRILLVGEPRVGKTSLIMSLVSEEFPEEVPPRAEEITIPADVTPERVPTHIVDYSE
  AEQSDEQLHQEISQANVICIVYAVNNKHSIDKVTSRWIPLINERTDKDSRLPLILVGNKS
  DLVEYSSMETILPIMNQYTEIETCVECSAKNLKNISELFYYAQKAVLHPTGPLYCPEEKE
  MKPACIKALTRIFKISDQDNDGTLNDAELNFFQRICFNTPLAPQALEDVKNVVRKHISDG
  VADSGLTLKGFLFLHTLFIQRGRHETTWTVLRRFGYDDDLDLTPEYLFPLLKIPPDCTTE
  LNHHAYLFLQSTFDKHDLDRDCALSPDELKDLFKVFPYIPWGPDVNNTVCTNERGWITYQ
  GFLSQWTLTTYLDVQRCLEYLGYLGYSILTEQESQASAVTVTRDKKIDLQKKQTQRNVFR
  CNVIGVKNCGKSGVLQALLGRNLMRQKKIREDHKSYYAINTVYVYGQEKYLLLHDISESE
  FLTEAEIICDVVCLVYDVSNPKSFEYCARIFKQHFMDSRIPCLIVAAKSDLHEVKQEYSI
  SPTDFCRKHKMPPPQAFTCNTADAPSKDIFVKLTTMAMYPHVTQADLKSSTFWLRASFGA
  TVFAVLGFAMYKALLKQR
• Function: Mitochondrial GTPase involved in mitochondrial trafficking. Probably involved in control of anterograde transport of mitochondria and their subcellular distribution. Promotes mitochondrial fission during high calcium conditions.
• Tissue Specificity: Ubiquitously expressed. Expressed at high level in heart and skeletal muscle.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway:
  RHOT1 GTPase cycle (R-HSA-9013425)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[2]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[1]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[4]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[5]
Pulmonary disease	DIS6060I	Limited	Biomarker	[6]
Stroke	DISX6UHX	Limited	Altered Expression	[7]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[5]

12 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 Mitochondrial Rho GTPase 1 (RHOT1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondrial Rho GTPase 1 (RHOT1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial Rho GTPase 1 (RHOT1).	[19]

References

• [1] Ectopic expression of Miro 1 ameliorates seizures and inhibits hippocampal neurodegeneration in a mouse model of pilocarpine epilepsy.Biochem Cell Biol. 2018 Aug;96(4):468-474. doi: 10.1139/bcb-2017-0102. Epub 2018 Jan 24.
• [2] Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase.J Biol Chem. 2014 May 23;289(21):14569-82. doi: 10.1074/jbc.M114.563031. Epub 2014 Mar 26.
• [3] Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models.Cell Metab. 2019 Dec 3;30(6):1131-1140.e7. doi: 10.1016/j.cmet.2019.08.023. Epub 2019 Sep 26.
• [4] Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels.Hum Mol Genet. 2017 Dec 1;26(23):4668-4679. doi: 10.1093/hmg/ddx348.
• [5] Inhibition of Miro1 disturbs mitophagy and pancreatic -cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes.Oncotarget. 2017 Sep 16;8(53):90693-90705. doi: 10.18632/oncotarget.20963. eCollection 2017 Oct 31.
• [6] Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke.Toxicol Lett. 2019 Dec 15;317:92-101. doi: 10.1016/j.toxlet.2019.09.022. Epub 2019 Oct 5.
• [7] Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery.Molecules. 2018 Mar 19;23(3):687. doi: 10.3390/molecules23030687.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] 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.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.