All ETDs from UAB

Advisory Committee Chair

John C Chatham

Advisory Committee Members

Scott W Ballinger

Victor M Darley-Usmar

Lori L McMahon

Martin E Young

Document Type

Thesis

Date of Award

2013

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic and ubiquitous posttranslational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc has emerged as an important regulator of cellular processes such as cell signaling, transcription, translation, apoptosis, and cell cycle regulation, among others. O-GlcNAc is thought to be a contributor to pathologies such as hyperglycemia and insulin resistance. O-GlcNAc has been viewed as an indicator of cellular energy levels and is associated with diabetic complications under nutrient excess. Other studies have shown that a variety of stress stimuli increase the levels of protein O-GlcNAc in mammalian cells, and this increase is associated with cytoprotection. Inhibiting O-GlcNAcylation decreased cell survival in response to stress, while increased O-GlcNAcylation augmented cell survival. Many of these studies demonstrated that this cytoprotection was associated with mitochondrial proteins. Compared to the nucleo-cytoplasm, much less work has been done in elucidating the potential role of O-GlcNAc in the mitochondria. In cardiac myocytes chronically exposed to high levels of glucose, complexes of the mitochondrial respiratory chain were shown to be O-GlcNAc modified. However these modifications were associated with impaired mitochondrial respiratory function. Hyperglycemia also induces mitochondrial superoxide production, which was shown to increase hexosamine biosynthesis and O- GlcNAcylation. Reactive oxygen species production can also lead to mitochondrial respiratory dysfunction and loss of mitochondrial membrane potential. It is possible that O-GlcNAcylation of respiratory chain complexes is involved in cardioprotection. While these results may seem contradictory, O-GlcNAcylation may simply be a constitutive element in non-pathological cellular functions, including oxidative phosphorylation, and perturbations in homeostatic O-GlcNAc signaling may lead to cell and mitochondrial dysfunction. Despite the current progress, the effect of O-GlcNAc on the many functions that mitochondria perform is still relatively unknown. It is increasingly apparent that mitochondrial proteins are O-GlcNAc modified and that this modification appears to modulate the function of these proteins.

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