Local Mitochondrial Fusion in Myelinated Axons In Vivo

描述（由申请人提供）：线粒体是一种动态细胞器，是细胞和轴突中主要的能量生产者。在过去的10年里，对线粒体特定行为的研究出现了爆炸式增长，称为线粒体重塑，指的是这些细胞器在融合和分裂中的活动。这些研究的主要新见解是，线粒体不仅产生能量，而且参与细胞杀伤和细胞拯救。一个重要的细胞拯救功能是通过线粒体融合来纠正线粒体DNA的错误。这项资助首次允许将线粒体重塑方面的知识应用于有髓神经生物学。关键是一种新技术，通过体内轴突中两个颜色编码的线粒体种群的碰撞来动态监测线粒体融合。这使我们能够解决髓鞘神经生物学的三个新领域，在健康和疾病方面具有重大意义。在病理领域，我们将检查是否应激刺激（神经横断和脱髓鞘）触发髓鞘轴突增加线粒体重塑活动。这将为进一步研究髓鞘轴突是否能够通过线粒体重塑局部修复线粒体DNA损伤奠定基础。在生理学领域，我们将研究线粒体重塑（融合）是否通过线粒体质量控制有助于有髓神经的代谢匹配。我们将研究代谢弱的线粒体是否可以通过与强线粒体融合而局部恢复活力，以及线粒体融合是否提高了神经活动期间Ranvier结募集的线粒体的质量。通过对髓鞘轴突严格局部线粒体融合的开创性研究，我们正在挖掘未被探索的轴突自主能力，这将刺激多发性硬化症（MS）的研究朝着新的治疗方向发展。我们能否促进轴突利用线粒体融合作为防御来修复线粒体DNA损伤并减缓这种疾病的神经退化，这种疾病在美国每10000名成年人中就有1人患病？

DESCRIPTION (provided by applicant): Mitochondria are dynamic organelles known to be the key energy producer in cells and axons. Within the last 10 years there has been an explosion of research in a specific mitochondrial behavior called mitochondrial remodeling, referring to the activity of these organelles in fusing and dividing. The major new insight from these studies is that mitochondria are not only producing energy, but are involved in cell killing and cell rescue. A significant cell rescue function is the correction of errors in mitochondrial DNA by mitochondrial fusion. This grant allows, for the first time, application of this knowledge in mitochondrial remodeling to myelinated nerve biology. The key is a new technique that dynamically monitors mitochondrial fusion through collision of two color-coded mitochondrial populations in axons in vivo. This allows us to address three new areas in myelinated nerve biology with major implications in health and in disease. In the area of pathology, we will examine if stressful stimuli (nerve transection and demyelination) trigger myelinated axons to increase mitochondrial remodeling activity. This will lay the groundwork for future studies to see whether myelinated axons can repair their mitochondrial DNA damage locally through mitochondrial remodeling. In the area of physiology, we will examine if mitochondrial remodeling (fusion) contributes to metabolic matching in myelinated nerves through mitochondrial quality control. We will examine whether metabolically weak mitochondria can be locally rejuvenated through fusion with strong mitochondria, and whether mitochondrial fusion improves the quality of mitochondria recruited by the node of Ranvier during nerve activity. By pioneering a study of strictly local mitochondrial fusion in myelinated axons, we are tapping into an unexplored autonomous ability of axons that will stimulate research in multiple sclerosis (MS) towards a novel therapeutic direction. Can we boost axons to use mitochondrial fusion as a defense to repair mitochondrial DNA damage and slow nerve degeneration in this disease that strikes ~ 1 in 10,000 adults in the US? PUBLIC HEALTH RELEVANCE: In this proposal, we examine local mitochondrial fusion activity in axons of myelinated nerves. This project is relevant to the metabolic health being of nerves, as well as to neuroprotection in multiple sclerosis.