All ETDs from UAB

Advisory Committee Chair

Aimee Landar

Advisory Committee Members

Scott Ballinger

Janusz Kabarowski

Matthew Renfrow

Victor Thannickal

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cells possess a remarkable plasticity to alter their metabolism and change their function based on stimuli within their resident microenvironment. The mitochondria within these cells utilize a variety of sources such as pyruvate, glutamine, or fatty acids in order to generate metabolites, amino acids, and reducing equivalents needed for cellular proliferation.Many mitochondrial enzymes possess contain a cysteine which possesses a thiol group, a unique redox-signaling moiety that can be activated under specific circumstances by bio-reactive compounds forming a network of mitochondrial proteins which are responsible for mitochondrial respiration. However, it is unknown whether targeting these reactive thiol groups present a unique stratagem to inhibit mitochondrial respiration of highly energetic cells, such as cancer cells. We therefore designed a series of targeted electrophiles to function as novel redox therapeutic agents, which are capable of modifying the mitochondrial protein thiol network. In this study, we observed that the lead compound, iodo-butyltriphenylphosphonium (IBTP), inhibited mitochondrial respiration, and decreased both adenonucleotides and metabolite levels, which are important for the generation of substrates required in cellular proliferation using the MDA-MB-231 adenocarcinoma cells (MB231). Additionally, we observed inactivation of the mitochondrial enzymes aconitase and decreased protein levels of the mitochondrial splice variant glutaminase C indicating that targeted thiol modification can disrupt mitochondrial function. This study is significant because it shows for the first time that the modulation of mitochondrial thiols can regulate mitochondrial respiration and cause decreases in cellular function. However, it was found that targeted electrophiles are not a viable redox therapy, at this stage of development, due to non-specific effects to immortalized nontumorigenic epithelial cells (MCF-10A). In summary, there is a lack of knowledge concerning how the mitochondrial protein thiol network plays a role in regulating mitochondrial respiration in the context of metabolic plasticity, and how modulation of thiols by endogenous or exogenous electrophiles are able to control cellular respiration.

Share

COinS