Modeling the iron storage protein ferritin reveals how residual ferrihydrite iron determines initial ferritin iron sequestration kinetics

Abstract

Computational models can be created more efficiently by composing them from smaller, well-defined sub-models that represent specific cellular structures that appear often in different contexts. Cellular iron metabolism is a prime example of this as multiple cell types tend to rely on a similar set of components (proteins and regulatory mechanisms) to ensure iron balance. One recurrent component, ferritin, is the primary iron storage protein in mammalian cells and is necessary for cellular iron homeostasis. Its ability to sequester iron protects cells from rising concentrations of ferrous iron limiting oxidative cell damage. The focus of the present work is establishing a model that tractably represents the ferritin iron sequestration kinetics such that it can be incorporated into larger cell models, in addition to contributing to the understanding of general ferritin iron sequestration dynamics within cells. The model’s parameter values were determined from published kinetic and binding experiments and the model was validated against independent data not used in its construction. Simulation results indicate that FT concentration is the most impactful on overall sequestration dynamics, while the FT iron saturation (number of iron atoms sequestered per FT cage) fine tunes the initial rates. Finally, because this model has a small number of reactions and species, was built to represent important details of FT kinetics, and has flexibility to include subtle changes in subunit composition, we propose it to be used as a building block in a variety of specific cell type models of iron metabolism.

Effects of Oral Iron Supplementation on Blood Iron Status in Athletes: A Systematic Review, Meta-Analysis and Meta-Regression of Randomized Controlled Trials

“…Iron status is regulated by various proteins, among which ferritin is an intracellular iron-binding protein and the primary storage of iron in the cells [ 51 ]. In steady-state conditions, the concentration of serum ferritin is correlated with iron stored in liver cells, which means measuring serum ferritin concentration enables the estimation of cellular iron stores [ 52 ].…”

Trace Metal Accumulation in Rats Exposed to Mine Waters: A Case Study, Bor Area (Serbia)

“…When there is an excess of iron in the diet or water, the body may prevent iron overload by decreasing the absorption of dietary Fe from the gastrointestinal tract [ 18 ], thus reducing the amount of iron available for distribution to various tissues, including the kidneys and testes [ 85 ]. In response to high Fe concentrations, the body may also increase the synthesis of iron-binding proteins like ferritin, sequestering excess iron and preventing its accumulation in tissues [ 86 ]. In addition, excess iron can compete with other metals, such as manganese, for absorption [ 18 , 48 ].…”

A kinetic model of iron trafficking in growing Saccharomyces cerevisiae cells; applying mathematical methods to minimize the problem of sparse data and generate viable autoregulatory mechanisms

“…i) Uniqueness: In principle each of the 9 rate-constants in the model could be regulated by any of the 8 model components. This afforded 8 9 = 134,217,728 possible CRMs. The first filter, called uniqueness, stipulated that the magnitude of k obs for a given reaction should be unique to a given cellular state; if not, the reaction need not be regulated.…”

“…Iron is essential in biology, and the import and function of this transition metal has been the subject of many previous computational studies [6][7][8][9][10][11]. In the current model, we wanted to simulate observed iron-associated changes in healthy iron-replete wild-type (WT) cells as they transitioned to either an iron-deficient state or to a diseased state in which expression of the yeast frataxin homolog 1 (Yfh1) protein is anomalously low.…”