Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8N4MRU)

• DOT Name: Mitochondrial proton/calcium exchanger protein (LETM1)
• Synonyms: Electroneutral mitochondrial K(+)/H(+)exchanger; KHE; Leucine zipper-EF-hand-containing transmembrane protein 1
• Gene Name: LETM1
• Related Disease:
  Intellectual disability
  Bladder cancer
  Esophageal squamous cell carcinoma
  Gastric adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
  Non-small-cell lung cancer
  Obesity
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Clear cell renal carcinoma
  Epilepsy
  Renal cell carcinoma
  Advanced cancer
  Colorectal adenocarcinoma
  Hepatocellular carcinoma
  Neoplasm
  Temporal lobe epilepsy
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: LETM1_HUMAN
• Pfam ID: PF07766
• Sequence:
  MASILLRSCRGRAPARLPPPPRYTVPRGSPGDPAHLSCASTLGLRNCLNVPFGCCTPIHP
  VYTSSRGDHLGCWALRPECLRIVSRAPWTSTSVGFVAVGPQCLPVRGWHSSRPVRDDSVV
  EKSLKSLKDKNKKLEEGGPVYSPPAEVVVKKSLGQRVLDELKHYYHGFRLLWIDTKIAAR
  MLWRILNGHSLTRRERRQFLRICADLFRLVPFLVFVVVPFMEFLLPVAVKLFPNMLPSTF
  ETQSLKEERLKKELRVKLELAKFLQDTIEEMALKNKAAKGSATKDFSVFFQKIRETGERP
  SNEEIMRFSKLFEDELTLDNLTRPQLVALCKLLELQSIGTNNFLRFQLTMRLRSIKADDK
  LIAEEGVDSLNVKELQAACRARGMRALGVTEDRLRGQLKQWLDLHLHQEIPTSLLILSRA
  MYLPDTLSPADQLKSTLQTLPEIVAKEAQVKVAEVEGEQVDNKAKLEATLQEEAAIQQEH
  REKELQKRSEVAKDFEPERVVAAPQRPGTEPQPEMPDTVLQSETLKDTAPVLEGLKEEEI
  TKEEIDILSDACSKLQEQKKSLTKEKEELELLKEDVQDYSEDLQEIKKELSKTGEEKYVE
  ESKASKRLTKRVQQMIGQIDGLISQLEMDQQAGKLAPANGMPTGENVISVAELINAMKQV
  KHIPESKLTSLAAALDENKDGKVNIDDLVKVIELVDKEDVHISTSQVAEIVATLEKEEKV
  EEKEKAKEKAEKEVAEVKS
• Function: Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport. Mediates proton-dependent calcium efflux from mitochondrion. Functions also as an electroneutral mitochondrial proton/potassium exchanger. Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain. Required for the maintenance of the tubular shape and cristae organization.
• Reactome Pathway:
  RHOG GTPase cycle (R-HSA-9013408)
  Mitochondrial calcium ion transport (R-HSA-8949215)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Lung neoplasm	DISVARNB	Strong	Biomarker	[5]
Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	DIS54M8C	Strong	Autosomal recessive	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Altered Expression	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[10]
Epilepsy	DISBB28L	moderate	Genetic Variation	[1]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]
Colorectal adenocarcinoma	DISPQOUB	Limited	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Therapeutic	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[13]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[14]
Thyroid gland carcinoma	DISMNGZ0	Limited	Altered Expression	[14]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[14]

2 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 proton/calcium exchanger protein (LETM1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial proton/calcium exchanger protein (LETM1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[21]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial proton/calcium exchanger protein (LETM1).	[25]

References

• [1] LETM1 is required for mitochondrial homeostasis and cellular viability (Review).Mol Med Rep. 2019 May;19(5):3367-3375. doi: 10.3892/mmr.2019.10041. Epub 2019 Mar 15.
• [2] Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells.Oncol Rep. 2017 Nov;38(5):2935-2940. doi: 10.3892/or.2017.5959. Epub 2017 Sep 18.
• [3] Identification of LETM1 as a marker of cancer stem-like cells and predictor of poor prognosis in esophageal squamous cell carcinoma.Hum Pathol. 2018 Nov;81:148-156. doi: 10.1016/j.humpath.2018.07.001. Epub 2018 Jul 18.
• [4] LETM1 is a potential biomarker that predicts poor prognosis in gastric adenocarcinoma.Exp Mol Pathol. 2020 Feb;112:104333. doi: 10.1016/j.yexmp.2019.104333. Epub 2019 Nov 6.
• [5] Suppression of lung tumorigenesis by leucine zipper/EF hand-containing transmembrane-1.PLoS One. 2010 Sep 2;5(9):e12535. doi: 10.1371/journal.pone.0012535.
• [6] Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization. Chin Med J (Engl). 2016 Mar 20;129(6):672-8. doi: 10.4103/0366-6999.177996.
• [7] LETM1 is a potential biomarker of prognosis in lung non-small cell carcinoma.BMC Cancer. 2019 Sep 9;19(1):898. doi: 10.1186/s12885-019-6128-9.
• [8] New players in high fat diet-induced obesity: LETM1 and CTMP.Metabolism. 2014 Mar;63(3):318-27. doi: 10.1016/j.metabol.2013.10.012. Epub 2013 Oct 31.
• [9] The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds.PLoS One. 2015 May 13;10(5):e0123173. doi: 10.1371/journal.pone.0123173. eCollection 2015.
• [10] Knockdown of LETM1 inhibits proliferation and metastasis of human renal cell carcinoma cells.Oncol Lett. 2018 Nov;16(5):6377-6382. doi: 10.3892/ol.2018.9449. Epub 2018 Sep 18.
• [11] LETM1 is a potential cancer stem-like cell marker and predicts poor prognosis in colorectal adenocarcinoma.Pathol Res Pract. 2019 Jul;215(7):152437. doi: 10.1016/j.prp.2019.152437. Epub 2019 May 5.
• [12] Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice.Cancer Gene Ther. 2013 Mar;20(3):186-94. doi: 10.1038/cgt.2013.6. Epub 2013 Feb 8.
• [13] Association of mitochondrial letm1 with epileptic seizures.Cereb Cortex. 2014 Oct;24(10):2533-40. doi: 10.1093/cercor/bht118. Epub 2013 May 3.
• [14] Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation.Oncotarget. 2016 Oct 11;7(41):66728-66739. doi: 10.18632/oncotarget.11456.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] 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.
• [21] 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.
• [22] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.