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Mathematical modeling of the dynamic storage of iron in ferritin

Salgado JC, Olivera-Nappa A, Gerdtzen ZP, Tapia V, Theil EC, Conca C, Nuñez MT - BMC Syst Biol (2010)

Bottom Line: Simulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels.Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP).The results presented support the role of ferritin as an iron buffer in a cellular system.

Affiliation: Laboratory of Process Modeling and Distributed Computing, Department of Chemical Engineering and Biotechnology, University of Chile, Santiago, Chile. jsalgado@ing.uchile.cl

ABSTRACT

Background: Iron is essential for the maintenance of basic cellular processes. In the regulation of its cellular levels, ferritin acts as the main intracellular iron storage protein. In this work we present a mathematical model for the dynamics of iron storage in ferritin during the process of intestinal iron absorption. A set of differential equations were established considering kinetic expressions for the main reactions and mass balances for ferritin, iron and a discrete population of ferritin species defined by their respective iron content.

Results: Simulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels. Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP). Ferritin stabilizes the cLIP for a wide range of total intracellular iron concentrations, but the model predicts an exponential increment of the cLIP at an iron content > 2,500 Fe/ferritin protein cage, when the storage capacity of ferritin is exceeded.

Conclusions: The results presented support the role of ferritin as an iron buffer in a cellular system. Moreover, the model predicts desirable characteristics for a buffer protein such as effective removal of excess iron, which keeps intracellular cLIP levels approximately constant even when large perturbations are introduced, and a freely available source of iron under iron starvation. In addition, the simulated dynamics of the iron removal process are extremely fast, with ferritin acting as a first defense against dangerous iron fluctuations and providing the time required by the cell to activate slower transcriptional regulation mechanisms and adapt to iron stress conditions. In summary, the model captures the complexity of the iron-ferritin equilibrium, and can be used for further theoretical exploration of the role of ferritin in the regulation of intracellular labile iron levels and, in particular, as a relevant regulator of transepithelial iron transport during the process of intestinal iron absorption.

Proposed mechanism for iron uptake/release by ferritin. Proposed mechanism for iron uptake/release by ferritin. (A) Iron (Fe) enters through a pore in the apoferritin protein cage structure (Fn(0)), forming an iron-ferritin complex (FeFn0) through a reversible process. (B) A series of redox reactions lead to iron incorporation into the mineral core of ferritin (Fn(1)). After n incorporation steps, the Ferritin species Fn(n) is obtained (C) Iron can be released from the mineral core through redox and transport processes. (D) Ferritin molecules can also be proteolytically degraded, returning their entire iron content to the cLIP during this process.
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Figure 7: Proposed mechanism for iron uptake/release by ferritin. Proposed mechanism for iron uptake/release by ferritin. (A) Iron (Fe) enters through a pore in the apoferritin protein cage structure (Fn(0)), forming an iron-ferritin complex (FeFn0) through a reversible process. (B) A series of redox reactions lead to iron incorporation into the mineral core of ferritin (Fn(1)). After n incorporation steps, the Ferritin species Fn(n) is obtained (C) Iron can be released from the mineral core through redox and transport processes. (D) Ferritin molecules can also be proteolytically degraded, returning their entire iron content to the cLIP during this process.

Mentions: Ferritin iron mineralization as a catalytic mechanism (see Figure 7), namely as a ferroxidase (EC 1.16.3.1), can be described applying usual enzymology mathematical tools, even though the process by which ferritins synthesize mineral and release iron is highly complex and not entirely understood [34].

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Mathematical modeling of the dynamic storage of iron in ferritin

Salgado JC, Olivera-Nappa A, Gerdtzen ZP, Tapia V, Theil EC, Conca C, Nuñez MT - BMC Syst Biol (2010)

Proposed mechanism for iron uptake/release by ferritin. Proposed mechanism for iron uptake/release by ferritin. (A) Iron (Fe) enters through a pore in the apoferritin protein cage structure (Fn(0)), forming an iron-ferritin complex (FeFn0) through a reversible process. (B) A series of redox reactions lead to iron incorporation into the mineral core of ferritin (Fn(1)). After n incorporation steps, the Ferritin species Fn(n) is obtained (C) Iron can be released from the mineral core through redox and transport processes. (D) Ferritin molecules can also be proteolytically degraded, returning their entire iron content to the cLIP during this process.
© Copyright Policy - open-access
Figure 7: Proposed mechanism for iron uptake/release by ferritin. Proposed mechanism for iron uptake/release by ferritin. (A) Iron (Fe) enters through a pore in the apoferritin protein cage structure (Fn(0)), forming an iron-ferritin complex (FeFn0) through a reversible process. (B) A series of redox reactions lead to iron incorporation into the mineral core of ferritin (Fn(1)). After n incorporation steps, the Ferritin species Fn(n) is obtained (C) Iron can be released from the mineral core through redox and transport processes. (D) Ferritin molecules can also be proteolytically degraded, returning their entire iron content to the cLIP during this process.
Mentions: Ferritin iron mineralization as a catalytic mechanism (see Figure 7), namely as a ferroxidase (EC 1.16.3.1), can be described applying usual enzymology mathematical tools, even though the process by which ferritins synthesize mineral and release iron is highly complex and not entirely understood [34].

Bottom Line: Simulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels.Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP).The results presented support the role of ferritin as an iron buffer in a cellular system.

Affiliation: Laboratory of Process Modeling and Distributed Computing, Department of Chemical Engineering and Biotechnology, University of Chile, Santiago, Chile. jsalgado@ing.uchile.cl

ABSTRACT

Background: Iron is essential for the maintenance of basic cellular processes. In the regulation of its cellular levels, ferritin acts as the main intracellular iron storage protein. In this work we present a mathematical model for the dynamics of iron storage in ferritin during the process of intestinal iron absorption. A set of differential equations were established considering kinetic expressions for the main reactions and mass balances for ferritin, iron and a discrete population of ferritin species defined by their respective iron content.

Results: Simulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels. Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP). Ferritin stabilizes the cLIP for a wide range of total intracellular iron concentrations, but the model predicts an exponential increment of the cLIP at an iron content > 2,500 Fe/ferritin protein cage, when the storage capacity of ferritin is exceeded.

Conclusions: The results presented support the role of ferritin as an iron buffer in a cellular system. Moreover, the model predicts desirable characteristics for a buffer protein such as effective removal of excess iron, which keeps intracellular cLIP levels approximately constant even when large perturbations are introduced, and a freely available source of iron under iron starvation. In addition, the simulated dynamics of the iron removal process are extremely fast, with ferritin acting as a first defense against dangerous iron fluctuations and providing the time required by the cell to activate slower transcriptional regulation mechanisms and adapt to iron stress conditions. In summary, the model captures the complexity of the iron-ferritin equilibrium, and can be used for further theoretical exploration of the role of ferritin in the regulation of intracellular labile iron levels and, in particular, as a relevant regulator of transepithelial iron transport during the process of intestinal iron absorption.

View Similar Images In: Results  - Collection
View Article: PubMed Central - HTML -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=2992510&rFormat=json&query=null&req=5