Details of Drug Off-Target (DOT)

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

• DOT Name: MICOS complex subunit MIC26 (APOO)
• Synonyms: Apolipoprotein O; MICOS complex subunit MIC23; Protein FAM121B
• Gene Name: APOO
• Related Disease:
  Acute coronary syndrome
  Cardiomyopathy
  Hepatocellular carcinoma
  Non-alcoholic fatty liver disease
  Obesity
  Mitochondrial disease
• UniProt ID: MIC26_HUMAN
• Pfam ID: PF09769
• Sequence:
  MFKVIQRSVGPASLSLLTFKVYAAPKKDSPPKNSVKVDELSLYSVPEGQSKYVEEARSQL
  EESISQLRHYCEPYTTWCQETYSQTKPKMQSLVQWGLDSYDYLQNAPPGFFPRLGVIGFA
  GLIGLLLARGSKIKKLVYPPGFMGLAASLYYPQQAIVFAQVSGERLYDWGLRGYIVIEDL
  WKENFQKPGNVKNSPGTK
• Function: Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Plays a crucial role in crista junction formation and mitochondrial function. Can promote cardiac lipotoxicity by enhancing mitochondrial respiration and fatty acid metabolism in cardiac myoblasts. Promotes cholesterol efflux from macrophage cells. Detected in HDL, LDL and VLDL. Secreted by a microsomal triglyceride transfer protein (MTTP)-dependent mechanism, probably as a VLDL-associated protein that is subsequently transferred to HDL.
• Tissue Specificity: Expressed in all tissues examined. Up-regulated in diabetic heart.
• Reactome Pathway: Cristae formation (R-HSA-8949613)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Altered Expression	[1]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Genetic Variation	[5]
Mitochondrial disease	DISKAHA3	Limited	X-linked	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of MICOS complex subunit MIC26 (APOO).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MICOS complex subunit MIC26 (APOO).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MICOS complex subunit MIC26 (APOO).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MICOS complex subunit MIC26 (APOO).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MICOS complex subunit MIC26 (APOO).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MICOS complex subunit MIC26 (APOO).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of MICOS complex subunit MIC26 (APOO).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of MICOS complex subunit MIC26 (APOO).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of MICOS complex subunit MIC26 (APOO).	[14]

References

• [1] Plasma apolipoprotein O level increased in the patients with acute coronary syndrome.J Lipid Res. 2012 Sep;53(9):1952-7. doi: 10.1194/jlr.P023028. Epub 2012 Jun 12.
• [2] Apolipoprotein O expression in mouse liver enhances hepatic lipid accumulation by impairing mitochondrial function.Biochem Biophys Res Commun. 2017 Sep 9;491(1):8-14. doi: 10.1016/j.bbrc.2017.06.128. Epub 2017 Jun 21.
• [3] Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line.Lipids Health Dis. 2013 Dec 17;12:186. doi: 10.1186/1476-511X-12-186.
• [4] Oleic acid induces the novel apolipoprotein O and reduces mitochondrial membrane potential in chicken and human hepatoma cells.Biochimie. 2018 Apr;147:136-142. doi: 10.1016/j.biochi.2018.02.003. Epub 2018 Feb 10.
• [5] Apolipoprotein O is mitochondrial and promotes lipotoxicity in heart.J Clin Invest. 2014 May;124(5):2277-86. doi: 10.1172/JCI74668. Epub 2014 Apr 17.
• [6] 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.
• [7] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] 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.
• [14] 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.
• [15] 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.