Semester

Fall

Date of Graduation

2022

Document Type

Thesis

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Candice Brown

Committee Co-Chair

Werner Geldenhuys

Committee Member

Bernard Schreurs

Committee Member

James Simpkins

Committee Member

Gordon Meares

Abstract

Oxidative stress is an imbalance between reactive oxygen species production and elimination, favoring the former. Reactive oxygen species serve as important signaling molecules for physiological homeostasis. However, when produced in excess, these once important signaling molecules become detrimental, disrupting cellular functions, and ultimately leading to cell death. In aging, reactive oxygen species production is increased, accompanied with reductions in oxidative stress resistance, increasing the risk for developing age-related diseases including cardiovascular disease, cancer, stroke, and neurodegenerative diseases. The outer mitochondrial membrane iron-sulfur cluster containing protein mitoNEET (CISD1; gene CISD1) has shown to be a mediator of mitochondrial function and oxidative stress. Groups have developed in vitro and in vivo models to study the loss of mitoNEET on cellular and physiological functions associated with aging, but as the field of mitoNEET research is fairly new, there are many questions that have yet to be explored. This dissertation investigates the influence of mitoNEET expression on age-related oxidative stress resistance to environmental stressors and in an Alzheimer’s disease model via genetic manipulations and pharmacological tools. To understand the effects of mitoNEET on age-related oxidative stress resistance to environmental stressors, transgenic mitoNEET knockout and overexpression Caenorhabditis elegans models were generated, aged, and exposed to the pro-oxidant paraquat. Upon paraquat exposure, mitoNEET overexpression models showed a reduction in overall oxidative stress and reactive oxygen species formation, supported by increases in mitochondrial superoxide dismutase expression and activation of the p38 mitogen activated protein kinase (MAPK) signaling cascade. With this understanding of the mechanisms by which mitoNEET overexpression attenuates oxidative stress, the next steps taken were to understand if preservation of mitoNEET expression provides the same benefits in an Alzheimer’s disease model. Alzheimer’s disease is a progressive, neurodegenerative disease, and the most common form of dementia. It is estimated that 6 million people in the U.S. are living with Alzheimer’s disease, with this number to more than double by 2060. While there are FDA-approved drugs for Alzheimer’s disease, there is no cure, and these drugs only slow the symptoms of disease progression. Studies have shown that oxidative stress contributes to the pathogenesis and progression of Alzheimer’s disease. Furthermore, mitoNEET has not been studied in models of Alzheimer’s disease. Therefore, the second study in this dissertation aimed to evaluate mitoNEET as a potential drug target to mediate oxidative stress in an Alzheimer’s disease C. elegans model that expresses the A��42 pathology using the novel thiazolidinedione-class mitoNEET agonist CI987. Investigation of CI987 showed elevated mitoNEET expression in both young and aged populations of C. elegans models of Alzheimer’s disease. Furthermore, CI987 treated populations showed reductions in oxidative stress and reactive oxidative species production, in part due to elevations in mitochondrial superoxide dismutase expression. Future efforts should investigate the reproducibility of these results in rodent models of Alzheimer’s disease, further analyzing the mechanisms of CI987 treatment on mitoNEET expression, and mitochondrial bioenergetics and function. In summary, this dissertation establishes a new direction in the field of aging and Alzheimer’s disease research, with the hope of using mitoNEET as a new target for the development of new drugs to combat neurodegeneration.


Embargo Reason

Publication Pending

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