title: HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis.
abstract: During prolonged hypoxia, hypoxia-inducible factors (HIFs) mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass and polycythemia. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. The molecular and biochemical mechanisms involved in neocytolysis are unknown. We developed a murine model of neocytolysis by exposing mice to 12 % oxygen for 10 days followed by return to normoxia. Upon return to normoxia, there was excessive accumulation of reactive oxygen species (ROS) in RBCs from an increased reticulocyte mitochondrial mass correlating with decreased Bnip3L transcripts (Bnip3L mediates reticulocyte mitophagy) and reduced catalase activity. During hypoxia, upregulated miR-21 resulted in low catalase activity in young RBCs. Furthermore, neocytolysis was attenuated by antioxidants and plasma catalase and blunted in mice that had constitutively high expression of HIFs. Among human neonates studied, we report data supporting the existence of neocytolysis during the first week of life. Together, these experiments indicate that the major mechanisms causing neocytolysis involve (1) production of young RBCs with low catalase during hypoxia and (2) lysis of the young RBCs after return to normoxia, mediated by ROS from an increased mitochondrial mass.
  
  
  CONCLUSIONS
  We report a mouse model of neocytolysis. Neocytolysis is caused by excessive ROS formation mediated by HIF. ROS is generated from increased mitochondria in reticulocytes. Hypoxia-generated RBCs have low catalase and are preferentially destroyed. Reduced catalase is regulated by increased microRNA-21.
authors.affiliation: Division of Hematology, School of Medicine, University of Utah, Salt Lake City, UT, 84132, USA.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
authors.forename: Donghoon
authors.initials: D
authors.lastname: Yoon
authors.forename: Robert D
authors.initials: RD
authors.lastname: Christensen
authors.forename: Monika
authors.initials: M
authors.lastname: Horvathova
authors.forename: Perumal
authors.initials: P
authors.lastname: Thiagarajan
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063306:Mitophagy; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012156:Reticulocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D002374:Catalase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C531950:MIRN21 microRNA, mouse