Author ORCID Identifier


Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation


Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Pramod K. Dash

Committee Member

M. Neal Waxham

Committee Member

Michael Beierlein

Committee Member

Jack C. Waymire

Committee Member

Anne B. Sereno

Committee Member

Jeffrey A. Frost


Mitochondrial dysfunction is a central feature in the pathophysiology of Traumatic Brain Injury (TBI). Loss of mitochondrial function disrupts normal cellular processes in the brain, as well as impedes the ability for repair and recovery, creating a vicious cycle that perpetuates damage after injury. To maintain metabolic homeostasis and cellular health, mitochondria constantly undergo regulated processes of fusion and fission and functionally adapt to changes in the cellular environment. An imbalance of these processes can disrupt the ability for mitochondria to functionally meet the metabolic needs of the cell, therefore resulting in mitochondrial damage and eventual cell death. Excessive fission, in particular, has been identified as a key pathological event in neuronal damage and death in many neurodegenerative disease models. Specifically, dysregulation of the primary protein regulator of mitochondrial fission, Dynamin-related Protein 1 (Drp1), has been implicated as an underlying mechanism associated with excessive fission and neurodegeneration; however, whether dysregulation of Drp1 and excessive fission occur after TBI and contribute to neuropathological outcome is not well known. The studies described in this dissertation investigate the following hypothesis: TBI causes dysregulation of Drp1 and increases mitochondrial fission in the hippocampus, and inhibiting Drp1 will reduce mitochondrial dysfunction, reduce neuronal damage, and improve cognitive function after injury. Results from these studies revealed four key findings: 1) Experimental TBI increases Drp1 association with mitochondria, and 2) causes acute changes in Drp1-mediated mitochondrial morphology that persists post-injury, indicating increased mitochondrial fission acutely after injury. Additionally, 3) post-injury treatment with a pharmacological inhibitor of Drp1, Mdivi-1, improved survival of newly born neurons in the injured hippocampus, and 4) improved hippocampal-dependent cognitive function after experimental TBI. Taken together, results from these studies reveal that TBI causes excessive Drp1-mediated mitochondrial fission and that this pathological fission state may play a key role in hippocampal neuronal death and cognitive deficits after TBI. Furthermore, these findings indicate inhibition of Drp1 and mitochondrial fission as a potential therapeutic strategy to improve neuronal recovery and cognitive function after injury.


Mitochondrial Fission, Drp1, Traumatic Brain Injury



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