title: Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease.
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.
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Jagadeeswaran
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Vazquez
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thiruppathi
authors.affiliation: Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Balaji B
authors.initials: BB
authors.lastname: Ganesh
authors.affiliation: Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Vinzon
authors.initials: V
authors.lastname: Ibanez
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Shuaiying
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Diamond
authors.affiliation: Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Molokie
authors.affiliation: Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.affiliation: Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Lavelle
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA. Electronic address: riversa@uic.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: Rivers
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012235:Rhodamines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C547335:RN1 compound; D017382:Reactive Oxygen Species; D012235:Rhodamines; D013141:Spiro Compounds; D013876:Thiophenes; D056466:Histone Demethylases; C495195:KDM1A protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus