title: SOD2 deficient erythroid cells up-regulate transferrin receptor and down-regulate mitochondrial biogenesis and metabolism.
abstract: BACKGROUND
  Mice irradiated and reconstituted with hematopoietic cells lacking manganese superoxide dismutase (SOD2) show a persistent hemolytic anemia similar to human sideroblastic anemia (SA), including characteristic intra-mitochondrial iron deposition. SA is primarily an acquired, clonal marrow disorder occurring in individuals over 60 years of age with uncertain etiology.
  
  
  RESULTS
  To define early events in the pathogenesis of this murine model of SA, we compared erythroid differentiation of Sod2⁻/⁻ and normal bone marrow cells using flow cytometry and gene expression profiling of erythroblasts. The predominant transcriptional differences observed include widespread down-regulation of mitochondrial metabolic pathways and mitochondrial biogenesis. Multiple nuclear encoded subunits of complexes I-IV of the electron transport chain, ATP synthase (complex V), TCA cycle and mitochondrial ribosomal proteins were coordinately down-regulated in Sod2⁻/⁻ erythroblasts. Despite iron accumulation within mitochondria, we found increased expression of transferrin receptor, Tfrc, at both the transcript and protein level in SOD2 deficient cells, suggesting deregulation of iron delivery. Interestingly, there was decreased expression of ABCb7, the gene responsible for X-linked hereditary SA with ataxia, a component required for iron-sulfur cluster biogenesis.
  
  
  CONCLUSIONS
  These results indicate that in erythroblasts, mitochondrial oxidative stress reduces expression of multiple nuclear genes encoding components of the respiratory chain, TCA cycle and mitochondrial protein synthesis. An additional target of particular relevance for SA is iron:sulfur cluster biosynthesis. By decreasing transcription of components of cluster synthesis machinery, both iron utilization and regulation of iron uptake are impacted, contributing to the sideroblastic phenotype.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Florent M
authors.initials: FM
authors.lastname: Martin
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.forename: Katharina
authors.initials: K
authors.lastname: von Löhneysen
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Gilmartin
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Friedman
mesh_terms: D000756:Anemia, Sideroblastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D004900:Erythroblasts / Q000378:metabolism / Q000502:physiology; D041905:Erythroid Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D011990:Receptors, Transferrin; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2