This study, primarily using Mössbauer spectroscopy, investigated the iron content of a yeast strain in which expression of Yeast Frataxin Homolog 1 (Yfh1), oxygenation conditions, iron concentrations, and metabolic modes were varied. Aerobic fermenting Yfh1-depleted cells were shown to grow slowly and accumulate Fe(III) nanoparticles, unlike WT cells. Under hypoxic conditions, the same mutant cells grew at rates similar to WT cells and had similar iron content, and were dominated by Fe(II) rather than Fe(III) nanoparticles. Furthermore, mitochondria from mutant hypoxic cells contained approximately the same levels of ISCs as WT cells, confirming that Yfh1 is not required for ISC assembly. These cells also did not accumulate excessive iron, indicating that iron accumulation into yfh1-deficient mitochondria is stimulated by O2. In addition, in aerobic WT cells, we found that vacuoles stored Fe(III), whereas under hypoxic fermenting conditions, vacuolar iron was reduced to Fe(II). Under respiring conditions, vacuoles of Yfh1-deficient cells contained Fe(III), and nanoparticles accumulated only under aerobic conditions. Taken together, these results informed a mathematical model of iron trafficking and regulation in cells that could semi-quantitatively simulate the Yfh1-deficiency phenotype. Simulations suggested partially independent regulation in which cellular iron import is regulated by ISC activity in mitochondria, mitochondrial iron import is regulated by a mitochondrial Fe(II) pool, and vacuolar iron import is regulated by cytosolic Fe(II) and mitochondrial ISC activity.

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