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Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease
- Source :
- Experimental Hematology. 50:46-52
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs), which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs retaining mitochondria in SCD patient blood samples compared with healthy individuals. In addition, using an experimental SCD mouse model, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention. Interestingly, the LSD1 inhibitor, RN-1, and the mitophagy-inducing agent mammalian target of rapamycin (mTOR) inhibitor, sirolimus, increased RBC lifespan and reduced ROS accumulation in parallel with reducing mitochondria-retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria-retaining RBCs may provide a new therapeutic approach to preventing excessive ROS in SCD.
- Subjects :
- 0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Cancer Research
Erythrocytes
Cell
Inflammation
Anemia, Sickle Cell
Thiophenes
Pharmacology
Mitochondrion
Biology
Models, Biological
Article
Mice
03 medical and health sciences
hemic and lymphatic diseases
Mitophagy
Genetics
medicine
Animals
Humans
Spiro Compounds
cardiovascular diseases
Molecular Biology
PI3K/AKT/mTOR pathway
Histone Demethylases
Sirolimus
Rhodamines
TOR Serine-Threonine Kinases
Cell Biology
Hematology
medicine.disease
Hemolysis
Mitochondria
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Immunology
Hemoglobin
medicine.symptom
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 0301472X
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Experimental Hematology
- Accession number :
- edsair.doi.dedup.....54eee662e455770741b9eb71023198eb