Distinct Mechanisms of Ferritin Delivery to Lysosomes in Iron-Depleted and Iron-Replete Cells

Abstract

Ferritin is a cytosolic protein that stores excess iron, thereby protecting cells from iron toxicity. Ferritinstored iron is believed to be utilized when cells become iron deficient; however, the mechanisms underlying the extraction of iron from ferritin have yet to be fully elucidated. Here, we demonstrate that ferritin is degraded in the lysosome under iron-depleted conditions and that the acidic environment of the lysosome is crucial for iron extraction from ferritin and utilization by cells. Ferritin was targeted for degradation in the lysosome even under iron-replete conditions in primary cells; however, the mechanisms underlying lysosomal targeting of ferritin were distinct under depleted and replete conditions. In iron-depleted cells, ferritin was targeted to the lysosome via a mechanism that involved autophagy. In contrast, lysosomal targeting of ferritin in iron-replete cells did not involve autophagy. The autophagy-independent pathway of ferritin delivery to lysosomes was deficient in several cancer-derived cells, and cancer-derived cell lines are more resistant to iron toxicity than primary cells. Collectively, these results suggest that ferritin trafficking may be differentially regulated by cell type and that loss of ferritin delivery to the lysosome under iron-replete conditions may be related to oncogenic cellular transformation.

Autophagy at the crossroads of catabolism and anabolism

“…The regulation of iron levels is maintained in cells by a network of iron-dependent proteins; upon iron depletion, its bioavailability is maintained via release from ferritin. Initial studies using Atg5 −/− fibroblasts revealed an important role for autophagy in ferritin degradation during iron depletion 108 . Subsequent ultrastructural studies in cells deficient in autophagy owing to the genetic deletion of either FIP200 or ATG9A revealed the accumulation of ferritin cluster particles at the autophagosome formation site 109 .…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The involvement of lysosomes in ferritin degradation and the concomitant iron release has been shown in different cell lines exposed to iron chelating agents (particularly deferoxamine (DFO) or overexpression of FtMt) (Kidane et al 2006;Zhang et al 2010), bacterial infection (Larson et al 2004), and ferroportin activation (Asano et al 2011). Lysosomal inhibitors, but not proteasomal inhibitors, could halt the degradation, induce ferritin accumulation in the organelles and block iron release.…”

“…Very recently a quantitative proteomic study identified the Nuclear Receptor Coactivator 4 (NCOA4) as a cargo receptor mediating ferritin delivery to the autophagosome (Mancias et al 2014), thus indicating a possible new level of regulation of cellular iron homeostasis. The intra-lysosomal degradation of ferritin has the advantage to shield the other cellular components by the potential toxicity of iron allowing a controlled release of the metal to the cytosol, where it increases LIP level (Asano et al 2011) and induces ferritin synthesis (Garner et al 1998). Nonetheless there are reports showing that ferritin, and particularly apo-and iron poorferritin, can be degraded also by the proteasome.…”

Apoferritin: protein nanocarrier for targeted delivery

“…Thus, lysosomal inhibitors can block ferritin degradation, with simultaneous accumulation of protein cages with iron in organelles. The intra-lysosomal degradation of ferritin shields the other cellular components from the potential toxicity of iron, allowing the controlled release of the metal into the cytosol, where it increases the labile iron pool level [19] and induces ferritin expression.…”

“…Ferritin is responsible for the storage and transfer of ferric ions, that can be toxic to the organism in higher doses [19]. The apoferritin protein shell is in the form of a hollow rhombic dodecahedron, created by 24 roughly cylindrical subunits of two types [20].…”