Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKYLK2J)

• DOT Name: ADP/ATP translocase 1 (SLC25A4)
• Synonyms: ADP,ATP carrier protein 1; ADP,ATP carrier protein, heart/skeletal muscle isoform T1; Adenine nucleotide translocator 1; ANT 1; Solute carrier family 25 member 4
• Gene Name: SLC25A4
• Related Disease:
  Mitochondrial disease
  Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive
  Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2
  Autosomal dominant progressive external ophthalmoplegia
  Sengers syndrome
  Leigh syndrome
• UniProt ID: ADT1_HUMAN
• Pfam ID: PF00153
• Sequence:
  MGDHAWSFLKDFLAGGVAAAVSKTAVAPIERVKLLLQVQHASKQISAEKQYKGIIDCVVR
  IPKEQGFLSFWRGNLANVIRYFPTQALNFAFKDKYKQLFLGGVDRHKQFWRYFAGNLASG
  GAAGATSLCFVYPLDFARTRLAADVGKGAAQREFHGLGDCIIKIFKSDGLRGLYQGFNVS
  VQGIIIYRAAYFGVYDTAKGMLPDPKNVHIFVSWMIAQSVTAVAGLVSYPFDTVRRRMMM
  QSGRKGADIMYTGTVDCWRKIAKDEGAKAFFKGAWSNVLRGMGGAFVLVLYDEIKKYV
• Function: ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane. In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity. Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it. Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death. It is however unclear if SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates it. Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1.
• Tissue Specificity: Expressed in erythrocytes (at protein level).
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Necroptosis (hsa04217)
  Cellular senescence (hsa04218)
  Neutrophil extracellular trap formation (hsa04613)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization (R-HSA-180897)
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive	DISXF87Q	Definitive	Autosomal recessive	[2]
Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant	DISH6GS5	Strong	Autosomal dominant	[3]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	DISFFUHN	Strong	Autosomal dominant	[4]
Autosomal dominant progressive external ophthalmoplegia	DISXBSXA	Supportive	Autosomal dominant	[5]
Sengers syndrome	DISV24KG	Supportive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	ADP/ATP translocase 1 (SLC25A4) increases the response to substance of Tretinoin.	[31]

24 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 ADP/ATP translocase 1 (SLC25A4).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADP/ATP translocase 1 (SLC25A4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ADP/ATP translocase 1 (SLC25A4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ADP/ATP translocase 1 (SLC25A4).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ADP/ATP translocase 1 (SLC25A4).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ADP/ATP translocase 1 (SLC25A4).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ADP/ATP translocase 1 (SLC25A4).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[17]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of ADP/ATP translocase 1 (SLC25A4).	[18]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[19]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of ADP/ATP translocase 1 (SLC25A4).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of ADP/ATP translocase 1 (SLC25A4).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ADP/ATP translocase 1 (SLC25A4).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of ADP/ATP translocase 1 (SLC25A4).	[28]
AHPN	DM8G6O4	Investigative	AHPN decreases the activity of ADP/ATP translocase 1 (SLC25A4).	[29]
Okadaic acid	DM47CO1	Investigative	Okadaic acid affects the expression of ADP/ATP translocase 1 (SLC25A4).	[30]

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 increases the methylation of ADP/ATP translocase 1 (SLC25A4).	[24]

References

• [1] Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy. J Med Genet. 2012 Feb;49(2):146-50. doi: 10.1136/jmedgenet-2011-100504. Epub 2011 Dec 20.
• [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] Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number. Am J Hum Genet. 2016 Oct 6;99(4):860-876. doi: 10.1016/j.ajhg.2016.08.014. Epub 2016 Sep 29.
• [4] A third locus predisposing to multiple deletions of mtDNA in autosomal dominant progressive external ophthalmoplegia. Am J Hum Genet. 1999 Jul;65(1):256-61. doi: 10.1086/302445.
• [5] SLC25A4 and C10ORF2 Mutations in Autosomal Dominant Progressive External Ophthalmoplegia. J Clin Neurol. 2011 Mar;7(1):25-30. doi: 10.3988/jcn.2011.7.1.25. Epub 2011 Mar 31.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [18] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [19] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [20] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] 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.
• [25] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [26] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [29] Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High-Throughput Screening of Transgenic Yeast. J Biomol Screen. 2016 Apr;21(4):381-90. doi: 10.1177/1087057115624637. Epub 2016 Jan 8.
• [30] Alterations in metabolism-related genes induced in SHSY5Y cells by okadaic acid exposure. J Toxicol Environ Health A. 2012;75(13-15):844-56. doi: 10.1080/15287394.2012.690703.
• [31] Apoptotic and anti-proliferative effects of all-trans retinoic acid. Adenine nucleotide translocase sensitizes HeLa cells to all-trans retinoic acid. Exp Cell Res. 2006 Jun 10;312(10):1813-9. doi: 10.1016/j.yexcr.2006.02.014. Epub 2006 Mar 23.