title: Over-expression of mitochondrial ferritin affects the JAK2/STAT5 pathway in K562 cells and causes mitochondrial iron accumulation.
abstract: BACKGROUND
  Mitochondrial ferritin is a nuclear encoded iron-storage protein localized in mitochondria. It has anti-oxidant properties related to its ferroxidase activity, and it is able to sequester iron avidly into the organelle. The protein has a tissue-specific pattern of expression and is also highly expressed in sideroblasts of patients affected by hereditary sideroblastic anemia and by refractory anemia with ringed sideroblasts. The present study examined whether mitochondrial ferritin has a role in the pathogenesis of these diseases.
  
  
  METHODS
  We analyzed the effect of mitochondrial ferritin over-expression on the JAK2/STAT5 pathway, on iron metabolism and on heme synthesis in erythroleukemic cell lines. Furthermore its effect on apoptosis was evaluated on human erythroid progenitors.
  
  
  RESULTS
  Data revealed that a high level of mitochondrial ferritin reduced reactive oxygen species and Stat5 phosphorylation while promoting mitochondrial iron loading and cytosolic iron starvation. The decline of Stat5 phosphorylation induced a decrease of the level of anti-apoptotic Bcl-xL transcript compared to that in control cells; however, transferrin receptor 1 transcript increased due to the activation of the iron responsive element/iron regulatory protein machinery. Also, high expression of mitochondrial ferritin increased apoptosis, limited heme synthesis and promoted the formation of Perls-positive granules, identified by electron microscopy as iron granules in mitochondria.
  
  
  CONCLUSIONS
  Our results provide evidence suggesting that Stat5-dependent transcriptional regulation is displaced by strong cytosolic iron starvation status induced by mitochondrial ferritin. The protein interferes with JAK2/STAT5 pathways and with the mechanism of mitochondrial iron accumulation.
authors.affiliation: Proteomics of Iron Metabolism Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Santambrogio
authors.forename: Benedetta Gaia
authors.initials: BG
authors.lastname: Erba
authors.forename: Alessandro
authors.initials: A
authors.lastname: Campanella
authors.forename: Anna
authors.initials: A
authors.lastname: Cozzi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Causarano
authors.forename: Laura
authors.initials: L
authors.lastname: Cremonesi
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.forename: Matteo Giovanni
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Rosangela
authors.initials: R
authors.lastname: Invernizzi
authors.forename: Sonia
authors.initials: S
authors.lastname: Levi
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005293:Ferritins / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020014:K562 Cells; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; D006418:Heme; D005293:Ferritins; D007501:Iron; D053614:Janus Kinase 2