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EOA Dissertation FINAL 12.21.21.pdf (3.22 MB)

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Understanding How O-GlcNAcylation and Phosphorylation Regulates the Mitochondrial Fission Machinery in Glioblastoma

Akinbiyi, Elizabeth O.
http://rave.ohiolink.edu/etdc/view?acc_num=case1639166650629381

Abstract Details

2022, Doctor of Philosophy, Case Western Reserve University, Pathology.
Mitochondrial dynamics, the fission and fusion of mitochondria, are vital to cellular health and homeostasis. Altered dynamics are associated with a number of diseases, one of which is the most aggressive and prevalent brain cancer, glioblastoma (GBM). Once diagnosed, patients live a median of less than 15 months with nearly all experiencing tumor recurrence, highlighting the need for therapeutic advancement. Also, increased mitochondrial fragmentation is often observed within the GBM stem cells (GSCs), known to be resistant to conventional therapies and believed to contribute to tumor recurrence. The mitochondrial fission machinery, dynamin-related protein-1 (Drp1) and mitochondrial fission factor (Mff), have both been implicated in contributing to the GBM disease state. To understand the altered regulation of these proteins in GBM, we investigate the post-translation modifications, O-GlcNAcylation and phosphorylation on them, respectively. We found that Drp1 O-GlcNAcylation and Mff phosphorylation were both increased in patient GSCs. Specifically, elevated O-GlcNAcylation of Drp1 correlated with increased mitochondrial fragmentation and mass, as well as altered mitochondrial ETC complex function. We also found that adenosine monophosphate (AMP)-activated protein kinase (AMPK) was the primary kinase phosphorylating Mff in one, but not all, of the GSC patient samples examined, demonstrating the importance of individual patient tumor profiling. Altogether, these studies demonstrate the importance of proper PTM regulation of Drp1and Mff in GBM, which may serve as future therapeutic points of intervention.
Jason Mears (Advisor)
Brian Cobb (Committee Chair)
Clive Hamlin (Committee Member)
Justin Lathia (Committee Member)
Ruth Keri (Committee Member)
169 p.
Biochemistry; Biology; Biomedical Research; Cellular Biology; Molecular Biology; Morphology; Science Education
Mitochondria; Mitochondrial Dynamics; Mitochondrial fission machinery; Dynamin-related protein-1 (Drp1); Mitochondrial fission factor (Mff); Oxidative Phosphorylation (OxPhos); Electron transport chain (ETC); O-GlcNAcylation; Phosphorylation; Glioblastoma (GBM); Mitochondrial morphology; adenosine triphosphate (ATP) content

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Citations

  • Akinbiyi, E. O. (2022). Understanding How O-GlcNAcylation and Phosphorylation Regulates the Mitochondrial Fission Machinery in Glioblastoma [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1639166650629381

    APA Style (7th edition)

  • Akinbiyi, Elizabeth. Understanding How O-GlcNAcylation and Phosphorylation Regulates the Mitochondrial Fission Machinery in Glioblastoma . 2022. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1639166650629381.

    MLA Style (8th edition)

  • Akinbiyi, Elizabeth. "Understanding How O-GlcNAcylation and Phosphorylation Regulates the Mitochondrial Fission Machinery in Glioblastoma ." Doctoral dissertation, Case Western Reserve University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=case1639166650629381

    Chicago Manual of Style (17th edition)

case1639166650629381
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