The Role of Compartmentalized Metabolism in Cellular Metal Homeostasis
type: CreativeWork
description: The building blocks of cells are usually thought to be DNA, RNA, and proteins. However, life, as we know it, is not possible without iron. While the list of iron's vital cellular functions is extensive, iron is also quite cytotoxic. Thus, great pains have been taken, at the gene regulation level, to assure that a cell has sufficient iron to copy its genome and power its mitochondria but not too much to damage its membranes with lipid peroxides. Cellular organelles, which accompanied the rise of atmospheric oxygen and an increased need for iron, also play a key role in iron homeostasis. Mitochondria are the sites of iron assimilation whereas lysosomes, with their v-ATPase-generated acidic lumens, are responsible for iron uptake and rely. In the first part of this work, I focused on lysosomes. Unbiased genetic screens performed on cells grown at sub-lethal levels of lysosomal pH inhibition identified several important metabolic pathways in this context. These included central carbon metabolism, cholesterol synthesis and iron homeostasis. While, cells starve for cholesterol and iron, only iron supplementation was necessary and sufficient to restore cell proliferation upon genetic or pharmacologic v-ATPase inhibition. Interestingly, iron supplementation rescued cell viability independent of lysosomal associated functions including signaling and endocytosis. It did, however, reverse changes resulting from low cellular iron including destabilized iron sulfur cluster proteins, induced hypoxia signaling, and impaired respiration. Finally, due to compromised aconitase activity, I identified an increased dependence on pyruvate-derived citrated as a metabolic ramification of lysosomal dysfunction. Taken together, this strongly argued that providing cellular iron is the essential function of lysosomal acidity for cell proliferation In the second part of this work, I explored other organelles in the setting of altered cellular iron. Using unbiased genetic screens, I found that i…
abstract: The building blocks of cells are usually thought to be DNA, RNA, and proteins. However, life, as we know it, is not possible without iron. While the list of iron's vital cellular functions is extensive, iron is also quite cytotoxic. Thus, great pains have been taken, at the gene regulation level, to assure that a cell has sufficient iron to copy its genome and power its mitochondria but not too much to damage its membranes with lipid peroxides. Cellular organelles, which accompanied the rise of atmospheric oxygen and an increased need for iron, also play a key role in iron homeostasis. Mitochondria are the sites of iron assimilation whereas lysosomes, with their v-ATPase-generated acidic lumens, are responsible for iron uptake and rely. In the first part of this work, I focused on lysosomes. Unbiased genetic screens performed on cells grown at sub-lethal levels of lysosomal pH inhibition identified several important metabolic pathways in this context. These included central carbon metabolism, cholesterol synthesis and iron homeostasis. While, cells starve for cholesterol and iron, only iron supplementation was necessary and sufficient to restore cell proliferation upon genetic or pharmacologic v-ATPase inhibition. Interestingly, iron supplementation rescued cell viability independent of lysosomal associated functions including signaling and endocytosis. It did, however, reverse changes resulting from low cellular iron including destabilized iron sulfur cluster proteins, induced hypoxia signaling, and impaired respiration. Finally, due to compromised aconitase activity, I identified an increased dependence on pyruvate-derived citrated as a metabolic ramification of lysosomal dysfunction. Taken together, this strongly argued that providing cellular iron is the essential function of lysosomal acidity for cell proliferation In the second part of this work, I explored other organelles in the setting of altered cellular iron. Using unbiased genetic screens, I found that i…
author: Weber, Ross A
keywords: iron, mitochondria, lysosomes, metabolism, cellular health, organelles, Life Sciences
date published: 2021-01-01T08:00:00Z
date modified: 2026-07-24T04:11:45Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller