Traumatic brain injury (TBI) remains a serious health concern in the United States, with nearly one out of every 100 people suffering a brain injury each year. Brain injury can result in debilitating damage to brain areas important for learning and memory, such as the hippocampus, causing long-lasting cognitive deficits and impairing one's ability to lead an independent life. Learning and memory impairments from TBI are caused by cellular dysfunction and death in the brain, partly due to persistent metabolic disturbances that may result from disruption of mitochondrial function. Mitochondria are constantly combining (i.e. fusion) and dividing (i.e. fission) based on the energy needs of the cell to regulate metabolic homeostasis and health. Mitochondrial fusion is regulated by the mitochondrial GTPases Optic Atrophy 1 (Opa1) and Mitofusins 1/2 (Mfn1/2), while fission is primarily regulated by the cytosolic GTPase, Dynamin-related Protein 1 (Drp1). Although mitochondrial fusion and fission are tightly balanced processes, if these events are not properly regulated, metabolic dysfunction, cellular damage, and death can occur. Excessive mitochondrial fission caused by aberrant Drp1 activity has been implicated in cell death and dysfunction in a number of neurodegenerative diseases. Excessive fission events diminish the ability for mitochondria to fuse and cause metabolic deficits similar to those seen after TBI. However, whether TBI alters Drp1 regulation of mitochondrial fission and contributes to TBI outcome has yet to be determined. Therefore, my working hypothesis is traumatic brain injury causes dysregulation of Drp1 and increases mitochondrial fission in the hippocampus, and inhibiting Drp1 will reduce mitochondrial dysfunction, decrease neuronal damage, and improve cognitive function after injury. To test my hypothesis, I will first determine if experimental TBI alters Drp1 and mitochondrial morphology in the hippocampus. Western blotting in combination with immuno-labeling and electron microscopy techniques will be employed to measure changes in protein levels, and translocation of Drp1 after TBI. I will next determine whether inhibiting Drp1 improves hippocampal outcome after experimental TBI. Using a pharmacological inhibitor of mitochondrial fission, the role of mitochondrial fission after brain injury will be examined through mitochondrial functional assays, hippocampal-dependent behavioral techniques, and histopathology of the hippocampus. By investigating pathological changes in mitochondrial fission, these studies will provide an innovative perspective on mechanisms of metabolic dysfunction and may lead to novel mitochondrial-targeted therapeutic approaches to improve patient outcome after brain injury.
Despite significant efforts in traumatic brain injury (TBI) research over the past several years, there has been limited success of neuroprotective interventions and patient outcomes remain poor after injury. Therefore, it is essential to understand the fundamental pathological mechanisms underlying TBI to develop novel therapeutic approaches and improve the quality of life in patients who suffer from brain injury. By investigating pathological changes in mitochondrial dynamics, these studies will advance our understanding on mechanisms of metabolic dysfunction that are essential for the development of potential therapeutic targets to improve patient outcome and quality of life after brain injury.
