Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8QBYZ0)

• DOT Name: Mitochondrial import receptor subunit TOM70 (TOMM70)
• Synonyms: Mitochondrial precursor proteins import receptor; Translocase of outer membrane 70 kDa subunit; Translocase of outer mitochondrial membrane protein 70
• Gene Name: TOMM70
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Alzheimer disease
  Autosomal dominant optic atrophy, classic form
  Hypothyroidism
  Myocardial infarction
  Neoplasm
  Nervous system disease
• UniProt ID: TOM70_HUMAN
• PDB ID: 7DHG; 7KDT
• Pfam ID: PF00515 ; PF13181
• Sequence:
  MAASKPVEAAVVAAAVPSSGSGVGGGGTAGPGTGGLPRWQLALAVGAPLLLGAGAIYLWS
  RQQRRREARGRGDASGLKRNSERKTPEGRASPAPGSGHPEGPGAHLDMNSLDRAQAAKNK
  GNKYFKAGKYEQAIQCYTEAISLCPTEKNVDLSTFYQNRAAAFEQLQKWKEVAQDCTKAV
  ELNPKYVKALFRRAKAHEKLDNKKECLEDVTAVCILEGFQNQQSMLLADKVLKLLGKEKA
  KEKYKNREPLMPSPQFIKSYFSSFTDDIISQPMLKGEKSDEDKDKEGEALEVKENSGYLK
  AKQYMEEENYDKIISECSKEIDAEGKYMAEALLLRATFYLLIGNANAAKPDLDKVISLKE
  ANVKLRANALIKRGSMYMQQQQPLLSTQDFNMAADIDPQNADVYHHRGQLKILLDQVEEA
  VADFDECIRLRPESALAQAQKCFALYRQAYTGNNSSQIQAAMKGFEEVIKKFPRCAEGYA
  LYAQALTDQQQFGKADEMYDKCIDLEPDNATTYVHKGLLQLQWKQDLDRGLELISKAIEI
  DNKCDFAYETMGTIEVQRGNMEKAIDMFNKAINLAKSEMEMAHLYSLCDAAHAQTEVAKK
  YGLKPPTL
• Function: Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex). Recognizes and mediates the translocation of mitochondrial preproteins from the cytosol into the mitochondria in a chaperone dependent manner. Mediates TBK1 and IRF3 activation induced by MAVS in response to Sendai virus infection and promotes host antiviral responses during virus infection. Upon Sendai virus infection, recruits HSP90AA1:IRF3:BAX in mitochondrion and the complex induces apoptosis.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway:
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  PINK1-PRKN Mediated Mitophagy (R-HSA-5205685)
  Ub-specific processing proteases (R-HSA-5689880)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  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
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[3]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Nervous system disease	DISJ7GGT	Limited	Autosomal dominant	[7]

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 import receptor subunit TOM70 (TOMM70).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitochondrial import receptor subunit TOM70 (TOMM70).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mitochondrial import receptor subunit TOM70 (TOMM70).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Mitochondrial import receptor subunit TOM70 (TOMM70).	[14]

References

• [1] Phosphoproteome mapping of cardiomyocyte mitochondria in a rat model of heart failure.Mol Cell Biochem. 2014 Apr;389(1-2):159-67. doi: 10.1007/s11010-013-1937-7. Epub 2014 Jan 7.
• [2] Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease.J Alzheimers Dis. 2018;61(2):793-801. doi: 10.3233/JAD-170613.
• [3] Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy.Cell Res. 2014 Aug;24(8):977-93. doi: 10.1038/cr.2014.94. Epub 2014 Jul 15.
• [4] Identification of a mammalian homologue of the fungal Tom70 mitochondrial precursor protein import receptor as a thyroid hormone-regulated gene in specific brain regions.J Neurochem. 1999 Dec;73(6):2240-9. doi: 10.1046/j.1471-4159.1999.0732240.x.
• [5] Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression.J Pineal Res. 2017 Jan;62(1). doi: 10.1111/jpi.12371. Epub 2016 Nov 1.
• [6] Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer.Cancer Res. 2017 Aug 1;77(15):4089-4101. doi: 10.1158/0008-5472.CAN-17-0785. Epub 2017 Jul 19.
• [7] 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.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [16] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.