Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome

Domenico, Ivana De; Vaughn, Michael B.; Li, Liangtao; Bagley, Dustin; Musci, Giovanni; Kaplan, Jerry

doi:10.1038/sj.emboj.7601409

Cited by 202 publications

(174 citation statements)

References 42 publications

(46 reference statements)

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…Indeed, oxidized ferritin is a target of proteasome degradation (Rudeck et al 2000) and lactacystin, a proteasome inhibitors, can increase ferritin stability in iron replete cells (Zhang et al 2010). The overexpression of ferroportin in HEK293 cells in iron replete conditions induced ferritin loss (but apparently not iron release) via ubiquitination and proteasome degradation (De Domenico et al 2006). Similar results were obtained exposing the same cells to deferasirox and deferiprone, chelating agents targeted to the cytosol, whereas DFO induced the lysosomal pathway (De Domenico et al 2009).…”

Section: Mammalian Ferritin Structurementioning

confidence: 67%

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

2014

View full text Add to dashboard Cite

Iron is an abundant transition metal that is essential for life, being associated to many enzyme and oxygen carrier proteins involved in a variety of fundamental cellular processes. At the same time the metal is potentially toxic due to its capacity to engage in the catalytic production of noxious reactive oxygen species. The control of iron availability in the cells is largely dependent on ferritins, ubiquitous proteins with storage and detoxification capacity. In mammals, cytosolic ferritins are composed of two types of subunits, the H and the L chain, assembled to form a 24-mer spherical cage. Ferritin is present also in mitochondria, in the form of a complex with 24 identical chains. Even though the proteins have been known for a long time, their study is a very active and interesting field yet. In this review we will focus our attention to mammalian cytosolic and mitochondrial ferritins, describing the most recent advancement regarding their storage and antioxidant function, the effects of their genetic mutations in human pathology, and also the possible involvement in non-iron related activities. We will also discuss recent evidence connecting ferritins and the toxicity of iron in a set of neurodegenerative disorder characterized by focal cerebral siderosis. IntroductionThe adaptation of life to an oxic environment required the development of mechanisms to deal with the transformation of the water soluble ferrous ion (Fe 2+ ) to the insoluble ferric ion (Fe 3+ ) and with the concomitant generation of dangerous reactive oxygen species (ROS). The ferritin molecules represent an important and ancient mean developed by organisms in the three domains of life to safely handle the necessary, yet potentially toxic metal. Their ability to detoxify and store the metal through safe oxidation processes protects the cells from undue iron-dependent redox chemistry, while a controlled release of the metal guarantees its availability for different and essential enzymatic reactions. Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this

show abstract

Section: Mammalian Ferritin Structurementioning

confidence: 67%

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

2014

View full text Add to dashboard Cite

show abstract

“…Iron is then relocated to the cytoplasm, probably by the participation of DMT1. Apart from the autophagic pathway, some ferritin is also degraded by proteasomes and these two pathways may be able to partially compensate for each other (De Domenico et al, 2006, De Domenico et al, 2009, Zhang et al, 2010. A less well documented, but still possible mechanism of iron release from ferritin is by way of pores in the ferritin molecules (Liu et al, 2003, Takagi et al, 1998.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

175

134

View full text Add to dashboard Cite

Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

show abstract

“…Recent data show that during iron deficiency in vivo, intact ferritin protein nanocages release iron into the cytoplasm of living cells [22], but the contribution of the conserved pore gates remains to be explored directly.…”

Section: Measuring the Opening Or Closing Of Gated Pores In Proteinsmentioning

confidence: 99%

Gated pores in the ferritin protein nanocage

Theil

Liu

Tosha

2008

Inorganica Chimica Acta

View full text Add to dashboard Cite

Synopsis and pictogram: Gated pores in the ferritin family of protein nanocages, illustrated in the pictogram, control transfer of ferrous iron into and out of the cages by regulating contact between hydrated ferric oxide mineral inside the protein cage, and reductants such as FMNH 2 on the outside. The structural and functional homology between the gated ion channel proteins in inaccessible membranes and gated ferritin pores in the stable, water soluble nanoprotein, make studies of ferritin pores models for gated pores in many ion channel proteins.Properties of ferritin gated pores, which control rates of FMNH 2 reduction of ferric iron in hydrated oxide minerals inside the protein nanocage, are discussed in terms of the conserved pore gate residues (arginine 72-apspartate 122 and leucine 110-leucine 134), of pore sensitivity to heat at temperatures 30 °C below that of the nanocage itself, and of pore sensitivity to physiological changes in urea (1-10 mM). Conditions which alter ferritin pore structure/function in solution, coupled with the high evolutionary conservation of the pore gates, suggest the presence of molecular regulators in vivo that recognize the pore gates and hold them either closed or open, depending on biological iron need. The apparent homology between ferrous ion transport through gated pores in the ferritin nanocage and ion transport through gated pores in ion channel proteins embedded in cell membranes, make studies of water soluble ferritin and the pore gating folding/unfolding a useful model for other gated pores.

show abstract

Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome

Cited by 202 publications

References 42 publications

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

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

The role of lysosomes in iron metabolism and recycling

Gated pores in the ferritin protein nanocage

Contact Info

Product

Resources

About