Uncovering the protective role of POLGD257A, a mitochondrial DNA mutator, on diabetes and obesity Public Deposited

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  • March 21, 2019
Creator
  • Fox, Raymond G.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Mitochondria are highly conserved organelles, found in most cells throughout the body, and perform many essential biological processes. Mitochondria are responsible for the production of energy in the form of ATP that is required to maintain normal function in eukaryotic cells. While this is beneficial to the cell, mitochondria have the unique role in initiating cell death. It is not surprising that mitochondrial dysfunction is the hallmark of many metabolic disorders such as maternally inherited diabetes and deafness. Some evidence suggests that mitochondrial dysfunction via mitochondrial DNA damage in the form of DNA deletions and mutations can contribute to complications associated with diabetes, yet a causal role of mitochondrial DNA mutations in diabetic complications has not been answered. The PolgD257A mutant mouse disrupts the proofreading domain of DNA polymerase gamma resulting in the random accumulation of mitochondrial DNA mutations. The research presented in this dissertation aims to utilize the PolgD257A mutant mouse as a genetic tool to further investigate the role that accumulating mitochondrial DNA mutations have in diabetes, obesity, and diabetic complications. I demonstrate that accumulating mitochondrial DNA mutations in "Akita" diabetic mice improves the diabetic phenotype of the male mice. Within this study, I determined that mitochondrial dysfunction in the testis reduces appetite thereby improving diabetes, underlining the importance of hyperphagia in the diabetic Akita mouse. Over the course of this study, I uncovered a phenotype of the small intestine that was not described previously. In a separate study, I characterized the small intestine phenotype demonstrating that the PolgD257A mutation disrupts the cell cycle of the rapidly dividing cells in the small intestine leading to an increase in cell death. While the small intestine phenotype does not seem to cause an observable phenotype in the PolgD257A mice, the final study investigated the functional aspect of the small intestine by challenging the mice with a high fat, high carbohydrate diet. The diet challenged mice were protected against obesity suggesting a role for mitochondria in normal lipid absorption. Together, these studies have elucidated the unexpected role of mitochondrial DNA mutations in reversing diabetes and preventing obesity.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy"
Advisor
  • Maeda, Nobuyo
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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