Photoreceptors, the neurons that initiate vision, must adapt to survive in a hostile cellular environment. In the retina they are exposed to damaging light radiation, experience 100-fold fluctuations in intracellular Ca2+, are located near blood vessels with high levels of O2, and use ATP faster than most other types of cells in the body. To ensure optimal function and survival, photoreceptors must have a robust system for maintaining healthy mitochondria. This would involve a regulated balance between mitochondrial clearance, biogenesis, fusion and fission. Here we propose a comprehensive analysis of the circadian regulation of these processes and how they relate to changes in mitochondrial structure and metabolic function. We exploit advantages of both the mouse and the zebrafish models and our expertise studying metabolism and photoreceptor biology.
In Aim 1 we will define daily and circadian changes in photoreceptor mitochondria function and structure.
In Aim 2 we evaluate mitochondrial clearance and biogenesis and in Aim 3 we examine cellular triggers underlying mitochondrial mobility. In summary, we are asking several questions that are all directed toward understanding mitochondria homeostasis. We will examine mitochondrial biogenesis, clearance, morphology, number, factors influencing motility and metabolism at different times of day both in light and dark. This will provide a broad and impactful overview of how these processes are coordinated to optimize photoreceptor health and function.
Malfunctioning mitochondria contribute to the pathogenesis of several diseases of the outer retina such as AMD, Stargardt disease, cone-rod dystrophies and Retinitis Pigmentosa. Understanding mitochondrial dynamics in photoreceptors will help prevent the dysfunction of this essential organelle. Maintaining healthy mitochondria can delay the onset and progression of photoreceptor degeneration.
|Giarmarco, Michelle M; Cleghorn, Whitney M; Hurley, James B et al. (2018) Preparing Fresh Retinal Slices from Adult Zebrafish for Ex Vivo Imaging Experiments. J Vis Exp :|
|Kanow, Mark A; Giarmarco, Michelle M; Jankowski, Connor Sr et al. (2017) Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. Elife 6:|
|Giarmarco, Michelle M; Cleghorn, Whitney M; Sloat, Stephanie R et al. (2017) Mitochondria Maintain Distinct Ca2+ Pools in Cone Photoreceptors. J Neurosci 37:2061-2072|
|Brockerhoff, Susan E (2017) Genome Editing to Study Ca2+ Homeostasis in Zebrafish Cone Photoreceptors. Adv Exp Med Biol 1016:91-100|