Non-transferrin-bound iron reaches mitochondria by a chelator-inaccessible mechanism: biological and clinical implications

Abstract

Non-transferrin-bound iron, commonly found in the plasma of iron-overloaded individuals, permeates into cells via pathways independent of the transferrin receptor. This may lead to excessive cellular accumulation of labile iron followed by oxidative damage and eventually organ failure. Mitochondria are the principal destination of iron in cells and a primary site of prooxidant generation, yet their mode of acquisition of iron is poorly understood. Using fluorescent probes sensitive to iron or to reactive oxygen species, targeted to cytosol and/or to mitochondria, we traced the ingress of labile iron into these compartments by fluorescence microscopy and quantitative fluorimetry. We observed that 1) penetration of non-transferrin-bound iron into the cytosol and subsequently into mitochondria occurs with barely detectable delay and 2) loading of the cytosol with high-affinity iron-binding chelators does not abrogate iron uptake into mitochondria. Therefore, a fraction of non-transferrin-bound iron acquired by cells reaches the mitochondria in a nonlabile form. The physiological role of occluded iron transfer might be to confer cells with a "safe and efficient cytosolic iron corridor" to mitochondria. However, such a mechanism might be deleterious in iron-overload conditions, because it could lead to surplus accumulation of iron in these critical organelles.

Deferasirox is a powerful NF- B inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging

“…In order to test whether deferasirox inhibition of NF-κB activity is dependent or not on cell iron deprivation by chelation, we added the highly membrane-permeant iron carrier FHQ 41 to the cells. K562 cells were incubated with deferasirox 50 μM alone or in combination with FHQ either 2.5 μM or 5μM.…”

“…Our attention was focused on the NF-κB pathway based on the important role of the transcription factor in the pathogenesis of MDS as Deferasirox inhibits NF-κB in MDS and AML cells haematologica | 2010; 95 (8) 1313 demonstrated in different studies 23,24 and on the observation that the efficacy of chemotherapeutic agents in AML cells is magnified adding specific NF-κB inhibitors in the in vitro model. 41 Moreover, the transcription factor activation is a particular characteristic of the blast cells, so the various compounds with NF-κB inhibitory activity are selectively targeted on the neoplastic clone. Due to such a selective property, inhibiting NF-κB, indeed, has no consequence in normal cells; thus, the pathway is not hyperactivated.…”

“…FHQ (ferric hydroxyquinoline, Sigma-Aldrich) was added to the medium at either 2.5 μM or 5 μM as previously described. 41 The NF-B inhibitor PS 1145 (Millenium, Cambridge, MA, USA) was added to the medium at 20 μM as previously described. 42 Incubated and control cells were both evaluated for NF-κB activity.…”

Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications

“…Ingress of ionic iron from the extracellular medium to the mitochondria of H9C2 cardiomyocytes was followed with the high-affinity Fe(II)-acceptor probe, RPA 22,23 (Figure 1). The hydrophobic cationic rhodamine B is responsible for RPA's potentiometric partitioning in the mitochondria, and phenanthroline is responsible for detection of Fe(II).…”

Conjugados de ovalbumina e albumina bovina com desferrioxamina e suas interações com íons metálicos

“…Os primeiros são conhecidos como NTBI (Non-Transferrin-Bound iron; ou ferro não-ligado à transferrina), de composição química indefinida, envolvendo formas com citrato ou albumina, podendo o metal ser monomérico ou oligomérico [4][5][6]. O reservatório citossólico é o LIP (labile iron pool; reservatório de ferro lábil), caracterizado pela presença de complexos do metal, quelado com ânions orgânicos, polipeptídios e componentes de membrana de superfície, em formas redox-ativas [7].…”