Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXP7MXN)

• DOT Name: Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44)
• Gene Name: TIMM44
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Diabetic kidney disease
  Diabetic retinopathy
  Non-insulin dependent diabetes
  Obesity
  Thyroid gland carcinoma
  Type-1/2 diabetes
  Neoplasm
  Thyroid cancer
• UniProt ID: TIM44_HUMAN
• PDB ID: 2CW9
• Pfam ID: PF04280
• Sequence:
  MAAAALRSGWCRCPRRCLGSGIQFLSSHNLPHGSTYQMRRPGGELPLSKSYSSGNRKGFL
  SGLLDNVKQELAKNKEMKESIKKFRDEARRLEESDVLQEARRKYKTIESETVRTSEVLRK
  KLGELTGTVKESLHEVSKSDLGRKIKEGVEEAAKTAKQSAESVSKGGEKLGRTAAFRALS
  QGVESVKKEIDDSVLGQTGPYRRPQRLRKRTEFAGDKFKEEKVFEPNEEALGVVLHKDSK
  WYQQWKDFKENNVVFNRFFEMKMKYDESDNAFIRASRALTDKVTDLLGGLFSKTEMSEVL
  TEILRVDPAFDKDRFLKQCENDIIPNVLEAMISGELDILKDWCYEATYSQLAHPIQQAKA
  LGLQFHSRILDIDNVDLAMGKMMEQGPVLIITFQAQLVMVVRNPKGEVVEGDPDKVLRML
  YVWALCRDQDELNPYAAWRLLDISASSTEQIL
• Function: Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. Recruits mitochondrial HSP70 to drive protein translocation into the matrix using ATP as an energy source.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[3]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Thyroid gland carcinoma	DISMNGZ0	Strong	Genetic Variation	[6]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]
Thyroid cancer	DIS3VLDH	Limited	Autosomal dominant	[9]

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 Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial import inner membrane translocase subunit TIM44 (TIMM44).	[24]

References

• [1] A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis.Aging (Albany NY). 2017 Oct 27;9(10):2098-2116. doi: 10.18632/aging.101304.
• [2] Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44.Gut. 2018 Feb;67(2):307-319. doi: 10.1136/gutjnl-2016-311909. Epub 2016 Nov 14.
• [3] Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production.J Am Soc Nephrol. 2006 Apr;17(4):1090-101. doi: 10.1681/ASN.2005111148. Epub 2006 Mar 1.
• [4] Diabetic retinopathy and damage to mitochondrial structure and transport machinery.Invest Ophthalmol Vis Sci. 2011 Nov 7;52(12):8739-46. doi: 10.1167/iovs.11-8045.
• [5] Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes.Metabolism. 2015 Jun;64(6):677-88. doi: 10.1016/j.metabol.2015.02.004. Epub 2015 Feb 23.
• [6] Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas.Br J Cancer. 2006 Dec 4;95(11):1529-36. doi: 10.1038/sj.bjc.6603455. Epub 2006 Oct 31.
• [7] Gene delivery of Tim44 reduces mitochondrial superoxide production and ameliorates neointimal proliferation of injured carotid artery in diabetic rats.Diabetes. 2005 Oct;54(10):2882-90. doi: 10.2337/diabetes.54.10.2882.
• [8] Read-through transcripts in normal human lung parenchyma are down-regulated in lung adenocarcinoma.Oncotarget. 2016 May 10;7(19):27889-98. doi: 10.18632/oncotarget.8556.
• [9] 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.
• [10] 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.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [23] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.