Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAAS85T)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23)
• Gene Name: TIMM23
• Related Disease:
  Parkinson disease
  Acute myocardial infarction
  Dilated cardiomyopathy 1A
  Hashimoto thyroiditis
  Huntington disease
  Kidney failure
  Tuberculosis
  Deafness dystonia syndrome
• UniProt ID: TIM23_HUMAN
• Pfam ID: PF02466
• Sequence:
  MEGGGGSGNKTTGGLAGFFGAGGAGYSHADLAGVPLTGMNPLSPYLNVDPRYLVQDTDEF
  ILPTGANKTRGRFELAFFTIGGCCMTGAAFGAMNGLRLGLKETQNMAWSKPRNVQILNMV
  TRQGALWANTLGSLALLYSAFGVIIEKTRGAEDDLNTVAAGTMTGMLYKCTGGLRGIARG
  GLTGLTLTSLYALYNNWEHMKGSLLQQSL
• Function: Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[3]
Hashimoto thyroiditis	DIS77CDF	Strong	Genetic Variation	[4]
Huntington disease	DISQPLA4	Strong	Altered Expression	[5]
Kidney failure	DISOVQ9P	Strong	Biomarker	[6]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[7]
Deafness dystonia syndrome	DIS0480U	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[15]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[17]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[21]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Mitochondrial import inner membrane translocase subunit Tim23 (TIMM23).	[22]

References

• [1] Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease.Cell Death Dis. 2018 Nov 7;9(11):1122. doi: 10.1038/s41419-018-1154-0.
• [2] Early Aerobic Exercise Combined with Hydrogen-Rich Saline as Preconditioning Protects Myocardial Injury Induced by Acute Myocardial Infarction in Rats.Appl Biochem Biotechnol. 2019 Mar;187(3):663-676. doi: 10.1007/s12010-018-2841-0. Epub 2018 Jul 23.
• [3] Role of Magmas in protein transport and human mitochondria biogenesis.Hum Mol Genet. 2010 Apr 1;19(7):1248-62. doi: 10.1093/hmg/ddq002. Epub 2010 Jan 6.
• [4] Genome-wide association analysis suggests novel loci underlying thyroid antibodies in Hashimoto's thyroiditis.Sci Rep. 2019 Mar 29;9(1):5360. doi: 10.1038/s41598-019-41850-6.
• [5] Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16593-16602. doi: 10.1073/pnas.1904101116. Epub 2019 Jul 25.
• [6] Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice.Biochem Pharmacol. 2019 Sep;167:116-124. doi: 10.1016/j.bcp.2019.07.003. Epub 2019 Jul 19.
• [7] Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.Autophagy. 2019 Mar;15(3):478-492. doi: 10.1080/15548627.2018.1522467. Epub 2018 Sep 22.
• [8] Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex.Hum Mol Genet. 2002 Mar 1;11(5):477-86. doi: 10.1093/hmg/11.5.477.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [18] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology. 2015 Aug 6;334:72-80.