Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

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, multis...

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Bibliographic Details
Published in:	Experimental hematology Vol. 50; pp. 46 - 52
Main Authors:	Jagadeeswaran, Ramasamy, Vazquez, Benjamin A, Thiruppathi, Muthusamy, Ganesh, Balaji B, Ibanez, Vinzon, Cui, Shuaiying, Engel, James D, Diamond, Alan M, Molokie, Robert E, DeSimone, Joseph, Lavelle, Donald, Rivers, Angela
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 01-06-2017
Subjects:	Advanced Basic Science Anemia, Sickle Cell - metabolism Animals Disease Models, Animal Erythrocytes - drug effects Erythrocytes - metabolism Hematology, Oncology and Palliative Medicine Histone Demethylases - metabolism Humans Mice Mitochondria - drug effects Mitochondria - metabolism Models, Biological Reactive Oxygen Species - metabolism Rhodamines - pharmacology Sirolimus - pharmacology Spiro Compounds - pharmacology Thiophenes - pharmacology TOR Serine-Threonine Kinases - metabolism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0301-472X 1873-2399
DOI:	10.1016/j.exphem.2017.02.003