The role of mitochondrial fission in TBI outcome

摘要 在美国，创伤性脑损伤(TBI)仍然是一个严重的健康问题，几乎每 每年有225人遭受脑损伤。额叶和颞叶对脑外伤和 这些区域的损害会导致无数的认知和行为障碍，包括学习和 记忆障碍。记忆力方面的问题会影响到保住工作、计划日常生活 活动，过独立的生活。脑外伤引起的记忆障碍可由死亡和功能障碍引起 驻留在海马体(位于颞叶核心的结构)和其他大脑中的细胞 结构。临床和实验研究都表明，代谢功能障碍和能量缺乏 损伤大脑中的产物会导致继发性损伤，阻碍修复，并导致不良结局。 线粒体是细胞的“能量发电站”，最近被证明是高度动态的。他们 根据细胞的能量需求，不断地结合(即融合)和分裂(即分裂)。线粒体 融合是由线粒体GTP酶视神经萎缩1(OPA1)和丝裂素(MFN)1/2调控的，而分裂是 主要受胞浆GTP酶动力蛋白相关蛋白1(Drp1)的调节。在健康细胞中，这两个 过程存在于动态平衡中。Drp1活性异常导致线粒体过度分裂 降低线粒体产生足够能量的能力，并与细胞死亡有关， 功能障碍和神经退化。这项拟议的研究旨在调查线粒体是否发生了变化 脑外伤后的神经病理改变和预后不良与动力学因素密切相关。我们假设TBI 增加损伤后离散时间窗口的线粒体裂变，并在此过程中减弱分裂 经期可增强线粒体功能，减少神经元损伤，改善认知功能。三 已经提出了具体的目标：目标1.确定线粒体动力学变化的时间进程 以及对雄性和雌性小鼠脑损伤后的功能影响。目标2.确定特定细胞的变化 颅脑损伤后线粒体形态变化。目的3.研究脑外伤后线粒体分裂是否减少 减少神经元丢失，改善记忆功能。通过研究线粒体的病理变化 动力学和功能，这些研究将为代谢机制提供一个创新的视角 在实验性脑外伤和人类患者中都会发生功能障碍，并可能导致新的线粒体- 有针对性的治疗方法，以改善患者的预后。

Abstract 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.