Abstract
While iron's unique coordination chemistry and redox activity have resulted in its broad incorporation into biological systems, dysfunction in key iron-regulating mechanisms can transform these biochemical advantages into factors that contribute to several pathological conditions. This dissertation explores the complex interactions between iron and sulfhydryl-containing compounds (SCCs), with particular focus on glutathione's (GSH) role in stabilizing iron reactivity juxtaposed with homocysteine's (Hcy) ability to disrupt iron homeostasis and promote disease progression. Through rigorous biochemical analysis and experimentation, we demonstrate that Hcy disrupts iron regulation through several mechanisms: (1) Hcy competitively displaces protective iron-binding molecules in the Labile Iron Pool (LIP), (2) Hcy transforms the LIP from a redox-inactive to a redox-active state, creating a destructive redox cycle that rapidly generates radical oxygen species (ROS), (3) Hcy both impairs ferritin (Ftn) loading and initiates Ftn unloading, dramatically lowering Ftn's storage capacity by up to 72%, (4) Hcy promotes the formation of magnetoferritin, a biomarker associated with neurodegenerative conditions, and (5) Hcy alters the expression of key iron-regulating proteins in a manner resembling ferroptosis. This work presents evidence for a direct mechanistic link between elevated Hcy levels and iron-mediated cellular damage, laying the foundation for understanding the correlation between hyperhomocysteinemia and various chronic inflammatory diseases, in particular neurodegenerative conditions. Understanding this Hcy-Fe axis of disease has significant implications for not only understanding iron-related pathology, but also offers new insight into novel intervention strategies for iron-associated conditions.
Degree
PhD
College and Department
Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry
Rights
https://lib.byu.edu/about/copyright/
BYU ScholarsArchive Citation
Christiansen, Steven Lowell Mann, "Sulfhydryl-Containing Compounds and Iron Homeostasis: Mechanisms of Labile Iron Pool Dysregulation and Consequences for Cellular Health" (2024). Theses and Dissertations. 10663.
https://scholarsarchive.byu.edu/etd/10663
Date Submitted
2024-12-12
Document Type
Dissertation
Handle
http://hdl.lib.byu.edu/1877/etd13500
Keywords
Homocysteine, Glutathione, Iron, Labile Iron Pool, Ferritin, Ferroptosis
Language
english