Traumatic brain injury (TBI) remains a serious health concern in the United States, with nearly one out of every 225 people suffering a brain injury each year. The frontal and temporal lobes are highly vulnerable to TBI and damage to these areas presents a myriad of cognitive and behavioral impairments including learning and memory dysfunction. Problems with memory can interfere with keeping a job, planning one's day-to-day activities, and living an independent life. Memory impairments from TBI can result from death and dysfunction of cells resident to the hippocampus (a structure that resides in the core of the temporal lobe) and other brain structures. Both clinical and experimental studies have shown that metabolic dysfunction and lack of energy production in the injured brain contribute to secondary injury, hinders repair and gives rise to poor outcome. Mitochondria are the ?energy powerhouses? of cells and have been recently shown to be highly dynamic. They constantly combine (i.e. fusion) and divide (i.e. fission) based on the energy needs of the cell. Mitochondrial fusion is regulated by the mitochondrial GTPases optic atrophy1 (Opa1) and mitofusin (Mfn)1/2, while fission is primarily regulated by the cytosolic GTPase dynamin-related protein1 (Drp1). In healthy cells, these two processes exist in a dynamic equilibrium. Excessive mitochondrial fission caused by aberrant Drp1 activity diminishes the ability of mitochondria to produce sufficient energy and has been implicated in cell death, dysfunction and neurodegeneration. The proposed research aims to investigate if altered mitochondrial dynamics plays a causal role in the neuronal pathology and poor outcome after TBI. We hypothesize that TBI increases mitochondrial fission for a discrete time widow following injury and that attenuating fission during this period will enhance mitochondrial function, decrease neuronal damage and improve cognitive function.
Three Specific Aims have been proposed:
Aim 1. To determine the time course for changes in mitochondrial dynamics and function following TBI in male and female mice.
Aim 2. To determine cell-specific changes in mitochondrial morphology after TBI.
Aim 3. Investigate if decreasing mitochondrial fission following TBI reduces neuronal loss and improves memory function. By investigating pathological changes in mitochondrial dynamics and function, these studies will provide an innovative perspective on mechanisms of metabolic dysfunction that occurs both in experimental TBI and human patients, and may lead to novel mitochondrial- targeted therapeutic approaches to improve patient outcome.
Traumatic brain injury (TBI) is a serious public health problem for which there is no cure. Much of the pathology associated with TBI can be linked to changes in the function of mitochondria, the organelles responsible for energy production. The current project will examine how TBI alters mitochondrial dynamics and will test potential therapeutic strategies. The results from these studies will further our understanding of the energy crisis of the injured brain and identify methods for its treatment.
