Details of Drug Off-Target (DOT)

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

• DOT Name: Mitochondria-eating protein (SPATA18)
• Synonyms: Spermatogenesis-associated protein 18
• Gene Name: SPATA18
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Ductal breast carcinoma in situ
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Limb-girdle muscular dystrophy
  Cardiomyopathy
• UniProt ID: MIEAP_HUMAN
• Pfam ID: PF16026
• Sequence:
  MAENLKRLVSNETLRTLQEKLDFWLKEYNTNTCDQNLNHCLELIEQVAKVQGQLFGILTA
  AAQEGGRNDGVETIKSRLLPWLEASFTAASLGKSVDSKVPSLQDTFDRERHKDPSPRDRD
  MQQLDSNLNSTRSQCNQVQDDLVETEKNLEESKNRSAISLLAAEEEINQLKKQLKSLQAQ
  EDARHRNTDQRSSENRRSEPWSLEERKREQWNSLKQNADQQDTEAMSDYKKQLRNLKEEI
  AVLSAEKSALQGRSSRSRSPSPAPRSRSCSRSRSASPSTAVKVRRPSPNRSKLSNVARKA
  ALLSRFSDSYSQARLDAQCLLRRCIDKAETVQRIIYIATVEAFHVAKMAFRHFKIHVRKS
  LTPSYVGSNDFENAVLDYVICHLDLYDSQSSVNDVIRAMNVNPKISFPPVVDFCLLSDFI
  QEICCIAFAMQALEPPLDIAYGADGEVFNDCKYRRSYDSDFTAPLVLYHVWPALMENDCV
  IMKGEAVTRRGAFWNSVRSVSRCRSRSLSPICPRSQIGLNTMSRSRSPSPIRCGLPRF
• Function: Key regulator of mitochondrial quality that mediates the repairing or degradation of unhealthy mitochondria in response to mitochondrial damage. Mediator of mitochondrial protein catabolic process (also named MALM) by mediating the degradation of damaged proteins inside mitochondria by promoting the accumulation in the mitochondrial matrix of hydrolases that are characteristic of the lysosomal lumen. Also involved in mitochondrion degradation of damaged mitochondria by promoting the formation of vacuole-like structures (named MIV), which engulf and degrade unhealthy mitochondria by accumulating lysosomes. The physical interaction of SPATA18/MIEAP, BNIP3 and BNIP3L/NIX at the mitochondrial outer membrane regulates the opening of a pore in the mitochondrial double membrane in order to mediate the translocation of lysosomal proteins from the cytoplasm to the mitochondrial matrix.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Biomarker	[4]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[5]

21 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 Mitochondria-eating protein (SPATA18).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondria-eating protein (SPATA18).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitochondria-eating protein (SPATA18).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondria-eating protein (SPATA18).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondria-eating protein (SPATA18).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondria-eating protein (SPATA18).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Mitochondria-eating protein (SPATA18).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mitochondria-eating protein (SPATA18).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mitochondria-eating protein (SPATA18).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mitochondria-eating protein (SPATA18).	[12]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Mitochondria-eating protein (SPATA18).	[15]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Mitochondria-eating protein (SPATA18).	[16]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Mitochondria-eating protein (SPATA18).	[17]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Mitochondria-eating protein (SPATA18).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondria-eating protein (SPATA18).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitochondria-eating protein (SPATA18).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondria-eating protein (SPATA18).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondria-eating protein (SPATA18).	[22]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Mitochondria-eating protein (SPATA18).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondria-eating protein (SPATA18).	[24]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Mitochondria-eating protein (SPATA18).	[25]

1 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 increases the phosphorylation of Mitochondria-eating protein (SPATA18).	[21]

References

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• [2] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [3] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [4] Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures.Hum Mutat. 2005 Sep;26(3):279-80. doi: 10.1002/humu.9357.
• [5] Gene expression changes in human iPSC-derived cardiomyocytes after X-ray irradiation.Int J Radiat Biol. 2018 Dec;94(12):1095-1103. doi: 10.1080/09553002.2018.1516908. Epub 2018 Sep 24.
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• [9] 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.
• [10] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] 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.
• [15] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [16] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [17] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [24] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [25] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.