Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors

Invernizzi, Rosangela; Travaglino, Erica; Porta, Matteo Giovanni Della; Gallì, Anna; Malcovati, Luca; Rosti, Vittorio; Bergamaschi, Gaetano; Erba, Benedetta Gaia; Bellistri, Francesca; Bastia, Raffaella; Santambrogio, Paolo; Levi, Sonia; Cazzola, Mario

doi:10.1111/bjh.12316

Cited by 11 publications

(12 citation statements)

References 48 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, down regulation of increased mitoferrin expression reversed mitochondrial iron accumulation and ameliorated nervous system degeneration in a Drosophila model of Friedreich’s ataxia [30]. In general, the mitochondrial iron deposits in these syndromes contain oxidized iron [31], though iron is sometimes found in mitochondrial ferritin, an iron storage molecule [32] [33] [34]. Many myelodysplastic syndromes with sideroblastic anemia are attributable to mutations in the splicing factor SF3B1 .…”

Section: The Mystery Of Mitochondrial Iron Overload Diseases- How Is mentioning

confidence: 99%

Mitochondrial iron overload: causes and consequences

Rouault

2016

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified.

show abstract

Section: The Mystery Of Mitochondrial Iron Overload Diseases- How Is mentioning

confidence: 99%

Mitochondrial iron overload: causes and consequences

Rouault

2016

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

show abstract

“…Interestingly, recent studies have demonstrated that subjects carrying GATA2-sequence variations have high risk to develop MDS 40 , suggesting that this pathogenetic event might be responsible for the up-regulation of FtMt in the disorder, where we have shown to interfere with JAK2/STAT5 pathways leading to ineffective erythropoiesis 27 28 .…”

Section: Discussionmentioning

confidence: 87%

“…In particular, GATA2 is a key transcriptional regulator of haematopoiesis, highly expressed in pluripotent hematopoietic stem cells and in early erythroid cells 40 . In physiological condition FtMt is not detectable in erythroid cells, while it is demonstrated that in pathological condition, like myelodysplastic syndrome with ring sideroblasts (MDS-RARS), it is specifically highly expressed in the ring- syderoblasts 4 21 28 . Actually, it exists a close correlation between the presence of FtMt and the iron specific Prussian blue staining indicating that mitochondrial ferritin is the form of iron deposited in perinuclear mitochondria of ring sideroblasts 28 .…”

Section: Discussionmentioning

confidence: 99%

“…A more recent study showed a downregulation of FTMT in Neuroblastoma and in Neurospongioma, where it has been proposed that FTMT could be used as a target to inhibit neuronal cell proliferation through its overexpression 26 . However, FTMT expression may also be detrimental, as showed in K562 erythroid cells where its overexpression reduced JAK/STAT signaling and increased apoptosis 27 28 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Guaraldo

Santambrogio

Rovelli

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Mitochondrial ferritin (FtMt) is an iron storage protein belonging to the ferritin family but, unlike the cytosolic ferritin, it has an iron-unrelated restricted tissue expression. FtMt appears to be preferentially expressed in cell types characterized by high metabolic activity and oxygen consumption, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. The human gene (FTMT) is intronless and its promoter region has not been described yet. To analyze the regulatory mechanisms controlling FTMT expression, we characterized the 5′ flanking region upstream the transcriptional starting site of FTMT by in silico enquiry of sequences conservation, DNA deletion analysis, and ChIP assay. The data revealed a minimal promoter region and identified the presence of SP1, CREB and YY1 as positive regulators, and GATA2, FoxA1 and C/EBPβ as inhibitors of the transcriptional regulation. Furthermore, the FTMT transcription is increased by acetylating and de-methylating agent treatments in K562 and HeLa cells. These treatments up-regulate FtMt expression even in fibroblasts derived from a Friedreich ataxia patient, where it might exert a beneficial effect against mitochondrial oxidative damage. The expression of FTMT appears regulated by a complex mechanism involving epigenetic events and interplay between transcription factors.

show abstract

“…More recently, it has been shown that overexpression of FtMt in K562 erythroid cells reduced Jak/STAT signaling and increased apoptosis [11]. In sideroblasts, erythroid progenitors FtMt expression occurred at the early stage of cell differentiation and was accompanied by reduced iron availability and increased apoptosis [12, 13]. Moreover, FtMt expressing cells transplanted in nude mice grew more slowly than their control counterpart [14].…”

Section: Introductionmentioning

confidence: 99%

Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity

et al. 2014

View full text Add to dashboard Cite

Mitochondrial ferritin is a functional ferritin that localizes in the mitochondria. It is expressed in the testis, heart, brain, and cells with active respiratory activity. Its overexpression in cultured cells protected against oxidative damage and reduced cytosolic iron availability. However, no overt phenotype was described in mice with inactivation of the FtMt gene. Here, we used the doxorubicin model of cardiac injury in a novel strain of FtMt-null mice to investigate the antioxidant role of FtMt. These mice did not show any evident phenotype, but after acute treatment to doxorubicin, they showed enhanced mortality and altered heart morphology with fibril disorganization and severe mitochondrial damage. Signs of mitochondrial damage were present also in mock-treated FtMt−/− mice. The hearts of saline- and doxorubicin-treated FtMt−/− mice had higher thiobarbituric acid reactive substance levels, heme oxygenase 1 expression, and protein oxidation, but did not differ from FtMt+/+ in the cardiac damage marker B-type natriuretic peptide (BNP), ATP levels, and apoptosis. However, the autophagy marker LC3 was activated. The results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of heart mitochondria to the toxicity of doxorubicin. This study represents the first in vivo evidence of the antioxidant role of FtMt.Key messageMitochondrial ferritin (FtMt) expressed in the heart has a protective antioxidant role.Acute treatment with doxorubicin caused the death of all FtMt−/− and only of 60 % FtMt+/+ mice.The hearts of FtMt−/− mice showed fibril disorganization and mitochondrial damage.Markers of oxidative damage and autophagy were increased in FtMt−/− hearts.This is the first in vivo evidence of the antioxidant role of FtMt.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1147-0) contains supplementary material, which is available to authorized users.

show abstract

Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors

Cited by 11 publications

References 48 publications

Mitochondrial iron overload: causes and consequences

Mitochondrial iron overload: causes and consequences

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity

Contact Info

Product

Resources

About