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Wofford, Joshua D (2018-12). Use of Mathematical Modeling and Other Biophysical Methods for Insights into Iron-Related Phenomena of Biological Systems. Doctoral Dissertation. | Thesis individual record

Iron is a crucial nutrient in most living systems. It forms the active centers of many
proteins that are critical for many cellular functions, either by themselves or as Fe-S clusters and
hemes. However, Fe is potentially toxic to the cell in high concentrations and must be tightly
regulated. There has been much work into understanding various pieces of Fe trafficking and
regulation, but integrating all of this information into a coherent model has proven difficult.

Past research has focused on different Fe species, including cytosolic labile Fe or
mitochondrial Fe-S clusters, as being the main regulator of Fe trafficking in yeast. Our initial
modeling efforts demonstrate that both cytosolic Fe and mitochondrial ISC assembly are
required for proper regulation. More recent modeling efforts involved a more rigorous multi
tiered approach. Model simulations were optimized against experimental results involving
respiring wild-type and Mrs3/4-deleted yeast. Simulations from both modeling studies suggest
that mitochondria possess a \"respiratory shield\" that prevents a vicious cycle of nanoparticle
formation, ISC loss, and subsequent loading of mitochondria with iron.

Work has also been done in understanding an accumulation of Fe in stationary grown
yeast cells. This accumulated Fe was found to be localized to the cell wall, and can be used as
cells are metabolically reactivating by being placed into fresh media. A mathematical model has
been developed to describe the metabolism of oxygen and nutrients in the autocatalytic
production of active cells, with subsequent deactivation of cells as nutrients became limiting.

E. coli have similar Fe contents relative to mitochondria, and they also appear to also
employ a \"respiratory shield\". This hypothesis was tested by either inhibiting respiratory
complexes with CN, or by growing cells into a metabolically inactive stationary growth state.
The generated nanoparticles were not associated with ferritins, which is surprising given that
much of the literature claims that ferritin Fe makes up a large portion of cellular Fe.

The iron content of murine hearts was also studied. Previous work from the Lindahl lab
focused on murine brains and livers, which contain ferritin at young and old ages, while losing it
in middle age. Hearts differ from these two organs, in that they mainly contain respiratory iron
sulfur clusters, and only gain ferritin as the mice approach old age.

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