Understanding mitochondrial movement and turnover in stressed and unstressed photoreceptors

摘要 光感受器是有丝分裂后的视网膜神经元， 必须保持健康和功能，以响应传入的光。在一生中， 光感受器需要大量的能量并且在各种应激源中是稳健的 包括高活性氧物质和光辐射。感光细胞功能障碍 线粒体可导致视力受损或完全丧失。揭露机制支持 压力期间的线粒体动力学将使我们了解光感受器的寿命。发展中 涉及线粒体功能障碍的视觉障碍的治疗首先需要了解 线粒体动力学在应激和非应激条件下的变化。斑马鱼是理想的模型 生物体作为它们的视锥光感受器含有一个大的线粒体簇，定位于 细胞体为了应对全天24小时的能量需求，线粒体簇 相应地增长或收缩。线粒体很少从这个簇移向 突触或感光细胞外。线粒体的存在定位于远离 集群在应激条件下增加。使不健康的线粒体远离健康的线粒体 集群可能是一种专门的应激反应，以保护光感受器。目前未知 光感受器线粒体是如何锚定或移动的。在本提案的目标1中，我将揭示 线粒体簇如何锚定在光感受器中以及线粒体如何挣脱 从该簇中移向突触。光感受器线粒体 在光感受器层外观察到一部分光感受器线粒体共定位 与穆勒胶质细胞。一些“错误定位”的感光细胞线粒体与Lysotracker共定位 光感受器层内外的绿色斑点表明线粒体更新。在aim中 2这个建议，我将确定细胞类型（S）负责感光线粒体 周转我预测，不健康的线粒体从簇中分离出来， 用缪勒胶质细胞机器翻转细胞。了解这种压力的机制 反应将深入了解光感受器如何在整个时间内保持稳健。这些发现 可以深入了解视网膜治疗如何针对线粒体功能障碍， 光感受器

ABSTRACT Required to visualize the world around us, photoreceptors are post-mitotic retinal neurons that must remain healthy and functional to respond to incoming light. Throughout a lifetime, photoreceptors require high amounts of energy and are robust amongst various stressors including high reactive oxygen species and light radiation. Dysfunctional photoreceptor mitochondria can lead to disrupted or complete vision loss. Uncovering mechanisms supporting mitochondrial dynamics during stress will yield insight into photoreceptor longevity. Developing therapies for visual disorders involving mitochondrial dysfunction first requires an understanding of mitochondrial dynamics in stressed and unstressed conditions. Zebrafish are ideal model organisms as their cone photoreceptors contain a large cluster of mitochondria localized to the cell body. In response to energy demands throughout the 24-hour day, the mitochondrial cluster grows or shrinks accordingly. Rarely mitochondria move away from this cluster towards the synapse or outside the photoreceptor cell. The presence of mitochondria localized away from the cluster is increased in stressed conditions. Moving unhealthy mitochondria away from the healthy cluster may be a specialized stress response to protect photoreceptors. It is currently unknown how photoreceptor mitochondria are anchored or move. In aim 1 of this proposal, I will uncover how the mitochondrial cluster is anchored in photoreceptors and how mitochondria can break free from that cluster and move towards the synapse. Photoreceptor mitochondria have been observed outside the photoreceptor layer and a portion of photoreceptor mitochondria colocalized with Müller glia. Some ‘mislocalized’ photoreceptor mitochondria colocalized with Lysotracker Green puncta within and outside the photoreceptor layer indicating mitochondrial turnover. In aim 2 of this proposal, I will determine the cell type(s) responsible for photoreceptor mitochondrial turnover. I predict that unhealthy mitochondria are separated from the cluster and ejected from the cell to be turned over by Müller glia machinery. Understanding the mechanisms of this stress response will give insight into how photoreceptors remain robust throughout time. These findings can yield insights into how retinal therapies can target mitochondrial dysfunction in photoreceptors.