A mathematical model of iron import and trafficking in wild-type and Mrs3/4\u0394\u0394 yeast cells

Joshua D Wofford,Paul A Lindahl

doi:10.1186/s12918-019-0702-2

Abstract

BackgroundIron plays crucial roles in the metabolism of eukaryotic cells. Much iron is trafficked into mitochondria where it is used for iron-sulfur cluster assembly and heme biosynthesis. A yeast strain in which Mrs3/4, the high-affinity iron importers on the mitochondrial inner membrane, are deleted exhibits a slow-growth phenotype when grown under iron-deficient conditions. However, these cells grow at WT rates under iron-sufficient conditions. The object of this study was to develop a mathematical model that could explain this recovery on the molecular level.ResultsA multi-tiered strategy was used to solve an ordinary-differential-equations-based mathematical model of iron import, trafficking, and regulation in growing Saccharomyces cerevisiae cells. At the simplest level of modeling, all iron in the cell was presumed to be a single species and the cell was considered to be a single homogeneous volume. Optimized parameters associated with the rate of iron import and the rate of dilution due to cell growth were determined. At the next level of complexity, the cell was divided into three regions, including cytosol, mitochondria, and vacuoles, each of which was presumed to contain a single form of iron. Optimized parameters associated with import into these regions were determined. At the final level of complexity, nine components were assumed within the same three cellular regions. Parameters obtained at simpler levels of complexity were used to help solve the more complex versions of the model; this was advantageous because the data used for solving the simpler model variants were more reliable and complete relative to those required for the more complex variants. The optimized full-complexity model simulated the observed phenotype of WT and Mrs3/4ΔΔ cells with acceptable fidelity, and the model exhibited some predictive power.ConclusionsThe developed model highlights the importance of an FeII mitochondrial pool and the necessary exclusion of O2 in the mitochondrial matrix for eukaryotic iron-sulfur cluster metabolism. Similar multi-tiered strategies could be used for any micronutrient in which concentrations and metabolic forms have been determined in different organelles within a growing eukaryotic cell.

Highlights

Iron plays crucial roles in the metabolism of eukaryotic cells
We have recently discovered a low-molecular-mass species in mitochondria, designated Fe580, which might serve as feedstock for iron-sulfur clusters (ISCs) assembly [21]
We have developed a simple model (Fig. 1, bottom panel) to illustrate the changes in iron import and trafficking that occur in ISC mutants relative to in WT cells [17]

Summary

Introduction

Iron plays crucial roles in the metabolism of eukaryotic cells. Much iron is trafficked into mitochondria where it is used for iron-sulfur cluster assembly and heme biosynthesis. A yeast strain in which Mrs3/4, the highaffinity iron importers on the mitochondrial inner membrane, are deleted exhibits a slow-growth phenotype when grown under iron-deficient conditions These cells grow at WT rates under iron-sufficient conditions. One means of analyzing such systems is to develop ordinary-differential-equation (ODE1)-based kinetic models [1,2,3] In principle, such models can reveal on a quantitative basis whether observed phenotypic behavior could emerge from a proposed system of reacting chemical players using a particular set of kinetic and thermodynamic parameters. This is a huge advantage relative to the common practice of describing complex biochemical processes as a cartoon or scheme.

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Conclusion