Details of Drug Off-Target (DOT)

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

• DOT Name: Transmembrane protein 70, mitochondrial (TMEM70)
• Gene Name: TMEM70
• Related Disease:
  Mitochondrial complex V (ATP synthase) deficiency nuclear type 2
  Mitochondrial disease
  3-methylglutaconic aciduria
  Barth syndrome
  Breast cancer
  Breast carcinoma
  Hypospadias
  Idiopathic cardiomyopathy
  Lactic acidosis
  Mitochondrial encephalomyopathy
  Myopathy
  Pulmonary arterial hypertension
  Adenoma
  Carcinoma
  Mitochondrial proton-transporting ATP synthase complex deficiency
  Cardiomyopathy
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Mitochondrial myopathy
• UniProt ID: TMM70_HUMAN
• Pfam ID: PF06979
• Sequence:
  MLFLALGSPWAVELPLCGRRTALCAAAALRGPRASVSRASSSSGPSGPVAGWSTGPSGAA
  RLLRRPGRAQIPVYWEGYVRFLNTPSDKSEDGRLIYTGNMARAVFGVKCFSYSTSLIGLT
  FLPYIFTQNNAISESVPLPIQIIFYGIMGSFTVITPVLLHFITKGYVIRLYHEATTDTYK
  AITYNAMLAETSTVFHQNDVKIPDAKHVFTTFYAKTKSLLVNPVLFPNREDYIHLMGYDK
  EEFILYMEETSEEKRHKDDK
• Function: Scaffold protein that participates in the c-ring assembly of mitochondrial ATP synthase (F(1)F(0) ATP synthase or complex V) by facilitating the membrane insertion and oligomer formation of the subunit c/ATP5MC1 through its interaction. Therefore, participates in the early stage of mitochondrial ATP synthase biogenesis and also protects subunit c/ATP5MC1 against intramitochondrial proteolysis. In addition, binds the mitochondrial proton-transporting ATP synthase complexes I and may play a role in the stability of its membrane-bound subassemblies.
• Tissue Specificity: Lower expressed in the heart than in the liver (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	DIS4YED2	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Genetic Variation	[3]
Barth syndrome	DISDI4KU	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[6]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[1]
Lactic acidosis	DISZI1ZK	Strong	Genetic Variation	[6]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Biomarker	[1]
Myopathy	DISOWG27	Strong	Genetic Variation	[6]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	moderate	Altered Expression	[7]
Carcinoma	DISH9F1N	moderate	Altered Expression	[7]
Mitochondrial proton-transporting ATP synthase complex deficiency	DISX6N3H	moderate	CausalMutation	[8]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[9]
Mitochondrial myopathy	DIS9SA7V	Limited	Genetic Variation	[10]

9 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 Transmembrane protein 70, mitochondrial (TMEM70).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Transmembrane protein 70, mitochondrial (TMEM70).	[19]

References

• [1] TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet. 2008 Nov;40(11):1288-90. doi: 10.1038/ng.246. Epub 2008 Oct 26.
• [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] Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.Mol Genet Metab. 2014 Mar;111(3):353-359. doi: 10.1016/j.ymgme.2014.01.001. Epub 2014 Jan 8.
• [4] Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.Am J Med Genet A. 2020 Jan;182(1):64-70. doi: 10.1002/ajmg.a.61383. Epub 2019 Nov 15.
• [5] Amplification of 8q21 in breast cancer is independent of MYC and associated with poor patient outcome.Mod Pathol. 2010 Apr;23(4):603-10. doi: 10.1038/modpathol.2010.5. Epub 2010 Feb 5.
• [6] Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation.Arch Dis Child. 2010 Apr;95(4):296-301. doi: 10.1136/adc.2009.168096.
• [7] Identification of epigenetically downregulated Tmem70 and Ube2e2 in rat liver after 28-day treatment with hepatocarcinogenic thioacetamide showing gene product downregulation in hepatocellular preneoplastic and neoplastic lesions produced by tumor promotion.Toxicol Lett. 2017 Jan 15;266:13-22. doi: 10.1016/j.toxlet.2016.11.022. Epub 2016 Nov 30.
• [8] TMEM70 deficiency: long-term outcome of 48 patients.J Inherit Metab Dis. 2015 May;38(3):417-26. doi: 10.1007/s10545-014-9774-8. Epub 2014 Oct 18.
• [9] Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70.Mol Genet Metab. 2010 Oct-Nov;101(2-3):282-5. doi: 10.1016/j.ymgme.2010.07.012. Epub 2010 Jul 24.
• [10] Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization.Mitochondrion. 2011 Jan;11(1):191-9. doi: 10.1016/j.mito.2010.09.008. Epub 2010 Oct 30.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [18] 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.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.