Neuronal mechanisms controlling number and function of presynaptic mitochondria

控制突触前线粒体数量和功能的神经机制

基本信息

批准号：
8734486
负责人：
GREGORY TALISKER MACLEOD
金额：
$ 30.32万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our overall goal is to elucidate the neuronal mechanisms that control mitochondria to satisfy the energy demands of nerve terminals. Mitochondria accumulate within nerve terminals where they generate most of the ATP required for the release and recycling of neurotransmitters. Neural function, therefore, relies on mitochondria generating sufficient ATP to sustain neurotransmitter release. Similarly, mitochondria power presynaptic Ca2+ homeostasis. A failure in neuronal Ca2+ homeostasis has catastrophic consequences and is a hallmark of many neurodegenerative diseases. Surprisingly, we know very little about the mechanisms that coordinate mitochondrial number and function with presynaptic energy requirements, yet understanding these mechanisms will be critical to understanding the progression of neurodegenerative disease. Our central hypothesis is that neuronal mechanisms control the number and function of mitochondria to accommodate presynaptic energy requirements, and that these mechanisms are synapse specific. We propose to elucidate these mechanisms in the musculoskeletal system of the fruit fly larva, where each motor neuron terminal has a different work rate which we can quantify using electrophysiological and Ca2+-imaging techniques. Diversity in presynaptic energy requirements, genetic tractability and accessibility to neurophysiological techniques, make this an ideal system in which to investigate neuronal mechanisms that control mitochondria to accommodate presynaptic energy requirements. In Aim 1, we will determine whether mitochondria are supplied to motor nerve terminals in numbers that are proportional to their work rate. 3D-EM reconstruction will be used to determine mitochondrial number. We will also probe the relationship between mitochondrial number and function. In Aim 2, we will test the hypothesis that mitochondrial volume is controlled at the level of different terminals on the same axon. Mitochondrial functional parameters will be determined at individual terminals to test whether mitochondrial function may be different between terminals on the same axon. In Aim 3, we will test the hypothesis that, over the course of development, active zone spacing and bouton diameter adjust to the firing rate of the motor neuron to bring presynaptic Ca2+ levels into a range most effective at stimulating mitochondrial energy metabolism during presynaptic activity. In so far as Ca2+ regulation is a heavy consumer of presynaptic ATP, this in situ model of presynaptic bioenergetics will provide an essential context for a better understanding of the early events involving mitochondrial dysfunction and Ca2+ dysregulation in neurodegenerative disease.

描述（由申请人提供）：我们的总体目标是阐明控制线粒体的神经元机制，以满足神经末端的能量需求。线粒体积聚在神经末端，它们产生释放和回收神经递质所需的大部分ATP。因此，神经功能依赖于线粒体产生足够的ATP来维持神经递质的释放。同样，线粒体功率突触前Ca2+稳态。神经元Ca2+稳态的失败会导致灾难性后果，并且是许多神经退行性疾病的标志。令人惊讶的是，我们对协调线粒体数和功能与突触前能量需求的机制知之甚少，但是了解这些机制对于理解神经退行性疾病的进展至关重要。我们的中心假设是神经元机制控制线粒体的数量和功能以适应突触前的能量需求，并且这些机制是突触特异的。我们建议在果蝇的肌肉骨骼系统中阐明这些机制，在果蝇的肌肉骨骼系统中，每个运动神经元末端的工作速率都不同，我们可以使用电生理学和CA2+成像技术来量化。突触前能量需求，遗传障碍性和对神经生理技术的可及性的多样性使这是研究控制线粒体以适应突触前能量需求的神经元机制的理想系统。在AIM 1中，我们将确定是否将线粒体提供给运动神经终端的数量与其工作率成正比。 3D-EM重建将用于确定线粒体数。我们还将探测线粒体数和功能之间的关系。在AIM 2中，我们将测试以下假设：线粒体体积在同一轴突上不同端子的水平上受到控制。线粒体功能参数将在单个端子上确定，以测试线粒体功能在同一轴突上的终端之间是否可能有所不同。在AIM 3中，我们将检验以下假设：在发育过程中，活动区间距和装束直径适应运动神经元的发射速率，以使突触前Ca2+水平在突触前活性期间最有效地刺激线粒体能量代谢中最有效。就CA2+调节而言，在突触前ATP的大量消费者中，这种原位突触前生物能学的原位模型将为更好地理解涉及线粒体功能障碍的早期事件和涉及神经退行性疾病的早期事件。