How Does Iron Get Into and Out of Ferritin?

Schematic overview

Getting in and out of ferritin. Iron enters ferritin through pores as Fe2+, where it is oxidized to Fe3+ and stored inside the shell. Iron exits ferritin through iron-regulatable NCOA4-mediated autophagic proteolytic degradation of the ferritin shell in lysosomes – a process called ferritinophagy. For larger view, click here.

How does iron enter the ferritin shell?

  • Ferrous ions (Fe2+) can diffuse into the core and enter the ferritin protein cage through 8 hydrophilic Fe2+ ion channels at the 3-fold symmetry axis, where they are oxidised by dioxygen (or H2O2 if present) at a di-iron catalytic site to form Fe(III)2–O products that then form the Fe2O3H2O.1

How does iron exit the ferritin shell?

  • The mechanism underlying the release of iron release from ferritin is called ferritinophagy, which is a form of autophagy.
  • Autophagy:2
    • A highly conserved process (present in all eukaryotes) that leads to degradation of cytoplasmic organelles, proteins, and macromolecules, and the recycling of the breakdown products.
    • In mammalian cells, there are three primary types of autophagy:3
      • Microautophagy
      • Macroautophagy
      • Chaperone-mediated autophagy (CMA)
    • All three types of autophagy culminate in the delivery of cargo to the lysosome for degradation and recycling.
    • The process of macroautophagy (of which ferritinophagy is an example) involves four sequential steps:4
      • Sequestration: The synthesis of double-membrane sequestering vesicles—autophagosomes—is used to sequester cargo and subsequently transport it to the lysosome.
      • Transfer: This takes place when the autophagosome is fused to a lysosome. Lysosomes contain enzymes that degrade dysfunctional components.
      • Degradation: This happens when a lysosome releases enzymes called hydrolases that break down the dysfunctional component.
      • Utilization/recycling: During this phase, the metabolites derived from the degradation step are repurposed as a fuel source for cells and synthesized into new proteins to maintain cells, rebuild cells, or create new cells.
A Diagram of the process of autophagy, which produces the structures autophagosomes (AP), and autolysosomes (AL). The membrane of the AP wraps around the cargo; thus, adjusting to fit the specific target. Once the autophagosome is formed, it must deliver its cargo to the lysosome. The outer membrane of the autophagosome will fuse with the lysosomal/vacuolar membrane. The product of fusion between an autophagosome and lysosome in mammalian cells is referred to as an autolysosome. Inside the AP, the autophagic cargo is degraded upon exposure to an acidic lumen and hydrolases. The component parts are then exported back into the cytoplasm through lysosomal permeases; B Electron micrograph of autophagic structures AP and AL in the fat body of a fruit fly larva; C Fluorescently-labeled autophagosomes AP in liver cells of starved mice. From Wikipedia.
Autophagy is a natural process by which a cell breaks down old, damaged, unnecessary, or dysfunctional components within a cell and then repurposes those components for fuel and to build or maintain cells. Source
Illustration showing the fusion of a lysosome (upper left) with an autophagosome during the process of autophagy. Source
  • Ferritinophagy:
    • Ferritinophagy refers to the selective autophagic turnover of ferritin by the lysosomes, leading to the degradation of the cytosolic iron storage complex ferritin in the autophagosome/lysosome, and resulting in the release of ferritin-bound iron as free iron.56
    • The process of ferritinophagy involves the selective autophagy cargo receptor nuclear receptor coactivator 4 (NCOA4).7
    • NCOA4 binds ferritin and targets it to the autophagosome,8 controlling ferritin flux through the ferritinophagy pathway.
    • NCOA4 is an iron-sensing protein whose levels are regulated by intracellular iron status:
      • When iron levels are high, NCOA4 abundance is low (it is ubiquitinated by ubiquitin ligase HERC2), thereby promoting ferritin accumulation and iron capture.
      • When intracellular iron levels are low, NCOA4 levels increase, resulting in ferritinophagy-mediated degradation of ferritin with release of ferric ions (Fe3+) and their subsequent conversion into ferrous ions (Fe2+).
    • NCOA4-deficient cells in vitro fail to activate ferritinophagy and are associated with decreased bioavailable iron.9
    • NCOA4-deficient mice demonstrate:10
      • Iron accumulation in the liver and spleen
      • Increased levels of:
        • Transferrin saturation
        • Serum ferritin
        • Liver hepcidin
      • Decreased levels of duodenal ferroportin
      • Mild microcytic hypochromic anemia
    • In summary:
      • Ferritinophagy is initiated by binding of NCOA4 to ferritin.
      • NCOA4 is a selective cargo receptor for autophagic turnover of ferritin.
      • NCOA4 acts as an iron sensor that is:
        • Degraded in condition of iron excess
        • Binds ferritin for the recycling of iron under conditions of iron starvation

For larger view, click here.
Ferritinophagy regulates iron homeostasis. Under conditions of iron deficiency, NCOA4 directly binds to FTH1 and then to LC3 to degrade ferritin, leading to iron release. Under normal iron levels and overload conditions, NCOA4 is ubiquitinated and degraded by HERC2, and ferritin is increased. When iron overload occurs, intracellular LIP increases, and ROS are generated through the Fenton reaction, which induces lipid peroxidation and participates in ferroptosis. Abbreviations: LIP, labile iron pool; ROS, reactive oxygen species. Journal of Nutritional Biochemistry 117 (2023) 109339.

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