The role of mitochondrial fission in TBI outcome

摘要 创伤性脑损伤（TBI）在美国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。额叶和颞叶非常容易受到TBI的影响， 对这些区域的损伤会导致无数的认知和行为障碍，包括学习和 记忆障碍记忆力的问题会影响工作，影响日常计划 活动，过独立的生活。脑外伤造成的记忆障碍可能是死亡和功能障碍造成的 海马体（一种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 在受伤的大脑中产生的有害物质会导致继发性损伤，阻碍修复并导致不良结果。 线粒体是细胞的“能量发电站”，最近已被证明是高度动态的。他们 基于细胞的能量需求不断地联合收割机（即融合）和分裂（即裂变）。线粒体 融合受线粒体GTP酶视神经萎缩1（Opa 1）和线粒体融合蛋白（Mfn）1/2调节，而分裂受线粒体GTP酶视神经萎缩1（Opa 1）和线粒体融合蛋白（Mfn）1/2调节。 主要由胞质GT3动力蛋白相关蛋白1（Drp 1）调节。在健康的细胞中，这两个 过程处于动态平衡中。异常Drp 1活性引起的线粒体过度分裂 降低了线粒体产生足够能量的能力并与细胞死亡有关， 功能障碍和神经变性。这项拟议中的研究旨在调查是否改变了线粒体 动力学在TBI后的神经元病理学和不良结果中起因果作用。我们假设创伤性脑损伤 在损伤后的离散时间窗内增加线粒体分裂， 月经周期将增强线粒体功能，减少神经元损伤，改善认知功能。三 提出了具体目标：目标1。为了确定线粒体动力学变化的时间过程， 以及雄性和雌性小鼠在TBI后的功能。目标2.为了确定细胞特异性变化， 脑外伤后线粒体形态。目标3。研究TBI后线粒体分裂是否减少 减少神经元损失并改善记忆功能。通过研究线粒体的病理变化， 动力学和功能，这些研究将提供一个创新的角度对机制的代谢 在实验性TBI和人类患者中发生的功能障碍，可能导致新的线粒体- 有针对性的治疗方法，以改善患者的结果。

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.