Advisory Committee Chair
John Chatham
Advisory Committee Members
Victor Darley-Usmar
Steven Lloyd
Jeonga Kim
Jianhua Zhang
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
The attachment of O-linked-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins has emerged as an important regulatory mechanism in transcriptional regulation, protein activation as well as cell survival. Several studies have reported that elevated O-GlcNAc levels have adverse effects on mitochondrial function. These negative effects have been linked to O-GlcNAc modification of mitochondrial proteins that are integral across multiple metabolic cell processes i.e. VDAC, NDUFA9 and DRP-1. Mitochondrial complexes I, III and IV all contain subunit proteins that are O-GlcNAc modified and increased O-GlcNAcylation of these proteins is associated with deficits in oxidative phosphorylation in these models. Conversely, it has also been reported that either manipulation of O-GlcNAc levels via inhibition of O-GlcNAcase (OGA), which catalyzes O-GlcNAc removal from proteins, or overexpression of O-GlcNAc transferase (OGT), which catalyzes O-GlcNAc addition to proteins, have no effect on mitochondrial function. Meanwhile our lab and others have shown that acute increases in O-GlcNAc can be cytoprotective against loss of mitochondrial membrane potential. Therefore the goal of this study was to better understand the effects of short-term increases in O-GlcNAcylation on mitochondrial function. This dissertation aims to address the following questions: 1) Does O-GlcNAcylation have a role in regulating mitochondrial oxidative stress response?, and 2) What is the role of O-GlcNAc on regulation of mitochondrial bioenergetics? In OGA inhibited immortal cells, we find that higher doses of OGA inhibition yield a time dependent decrease in mitochondrial oxygen consumption rates (OCR). Significant decreases in complex I, II and IV function, accumulations in complex subunit proteins, and decreases in levels of critical mitochondrial protease, LonP1, were associated with this decrease in OCR. These changes show for the first time the limits of O-GlcNAc mediated regulation of metabolic function in an acute manner that may be disrupted when levels are maximally induced and/or maintained for longer periods of time. Taken together, these data support the concept that there are changes in mitochondrial function as a response to increasing O-GlcNAc levels; and provide new information regarding how this regulation influences mitochondrial response to cellular stress.
Recommended Citation
Wright, Jalessa Nicole, "The Role of Protein O-GlcNAcylation in Regulating Mitochondrial Function" (2019). All ETDs from UAB. 3379.
https://digitalcommons.library.uab.edu/etd-collection/3379