Illuminating Mechanisms of Nuclear and Mitochondrial Heme Dynamics
Author(s)
Willoughby, Mathilda
Advisor(s)
Reddi, Amit
Editor(s)
Collections
Supplementary to:
Permanent Link
Abstract
Heme is an essential yet inherently cytotoxic metallocofactor. In the field, heme has traditionally been viewed as a static cofactor, buried in enzymes. The development and availability of new technologies and unique sensors has created opportunities to understand the role of heme, its complex dynamics, and its broader role as a signaling molecule. Indeed, heme must be safely mobilized from sites of synthesis or uptake to target proteins across the cell.
Heme is a potentially toxic, hydrophobic, and pro-oxidative molecule. This necessitates the cell tightly regulates heme (synthesis, uptake, trafficking, degradation, and export) to limit detrimental interactions with off-target proteins and membranes. However, molecules and mechanisms that regulate intracellular heme bioavailability (transport, trafficking) to and within virtually every subcellular compartment are not well understood.
Herein, this thesis combines the use of fluorescent heme sensors, genetic screens, and biochemical techniques to identify and characterize heme trafficking factors that control heme bioavailability. Doing so will enhance our understanding of heme implications in diseases such as Alzheimer’s, Anemias, Porphyrias, Cardiovascular, and Cancers, and the development of better and improved therapies.1
This comprehensive work integrates fluorescent heme sensors and genetics to probe the labile heme pool to identify and elucidate heme trafficking and heme homeostasis pathways. Specifically, we aim to further elucidate 1) factors that aid in mitochondrial heme export, 2) factors that regulate steady-state nuclear heme availability, and 3) the relationship between heme utilization and bioavailability.
Sponsor
Date
2023-07-27
Extent
Resource Type
Text
Resource Subtype
Dissertation