Understanding mitochondrial movement and turnover in stressed and unstressed photoreceptors

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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.