title: Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors.
abstract: In myelodysplastic syndromes with ring sideroblasts (MDS-RS), the iron deposited in the mitochondria of RS is present in the form of mitochondrial ferritin (FTMT), but it is unknown whether FTMT overexpression is the cause or the result of mitochondrial iron deposition. Lentivirus FTMT-transduced CD34(+) bone marrow cells from seven healthy donors and CD34(+) cells from 24 patients with MDS-RS were cultured according to a procedure that allowed the expansion of high numbers of erythroid progenitors. These cells were used to investigate the possible influence of experimentally-induced FTMT overexpression on normal erythropoiesis and the functional effects of FTMT in sideroblastic erythropoiesis. In MDS-RS progenitors, FTMT overexpression was associated with reduced cytosolic ferritin levels, increased surface transferrin receptor expression and reduced cell proliferation; FTMT effects were independent of SF3B1 mutation status. Similarly, FTMT overexpressing normal erythroid progenitors were characterized by reduced cytosolic ferritin content and increased CD71 expression, and also by higher apoptotic rate in comparison with the FTMT- controls. Significantly lower levels of STAT5 phosphorylation following erythropoietin stimulation were found in both sideroblastic and normal FTMT(+) erythroid cells compared to the FTMT- cells. In conclusion, experimental overexpression of FTMT may modify mitochondrial iron availability and lead to ineffective erythropoiesis.
authors.affiliation: Department of Internal Medicine, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Rosangela
authors.initials: R
authors.lastname: Invernizzi
authors.affiliation: Department of Haematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Travaglino
authors.affiliation: Department of Haematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.affiliation: Department of Haematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.affiliation: Department of Haematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Unit of Clinical Epidemiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Department of Internal Medicine, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Bergamaschi
authors.affiliation: Proteomics of Iron Metabolism Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Benedetta G
authors.initials: BG
authors.lastname: Erba
authors.affiliation: Department of Internal Medicine, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bellistri
authors.affiliation: Department of Internal Medicine, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bastia
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.affiliation: Proteomics of Iron Metabolism Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy.|Vita-Salute San Raffaele University, Milano, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Levi
authors.affiliation: Department of Haematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000756:Anemia, Sideroblastic / Q000378:metabolism* / Q000473:pathology; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology; D005260:Female; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; D024101:Mitochondrial Proteins; C556634:mitochondrial ferritin, human; D005293:Ferritins