The viability and function of neurons rely on proper control of metabolic energy.
The aim of this proposal is to understand how metabolic energy is produced and distributed in photoreceptors. We are investigating the mechanisms by which these neurons respond to the changing temporal and spatial energy demands of darkness and light. In a recent study we discovered fundamental new information about how energy flows in a photoreceptor in darkness and light. We showed that in darkness energy flows from the cell body toward the synaptic terminal. ATP in the cell body is converted to phosphocreatine by a mitochondrial creatine kinase. This traps the energy in a form that is protected from consumption by ion pumps as it diffuses to the synaptic terminal. At the terminal another isoform of creatine kinase transfers the energy from phosphocreatine back into ATP to support synaptic transmission. In light ATP produced from the cell body flows in the opposite direction to the outer segment where it is used directly to support phototransduction. Based on this new model for energy distribution we will pursue three specific aims. The first is to identify the mechanism that sequesters creatine kinase at the synaptic terminal. The second is to determine the distributions of glycolytic enzymes in photoreceptors. The third is to investigate how mitochondria in photoreceptors are regulated to keep pace with the quantitatively and qualitatively different energy demands of light and darkness. Knowledge of how energy is produced and distributed is of fundamental importance for understanding how photoreceptors function and remain viable.
Inherited retinal degeneration is a leading cause of blindness. The biochemical pathway that links mutation to cell death is not yet understood for any form of inherited retinal degeneration. Mitochondria can initiate cell death, so it is likely that mis-regulation of mitochondrial activity contributes to many forms of retinal degeneration. Not enough is known about energy metabolism in photoreceptors. The aim of this proposal is to build a foundation of knowledge about photoreceptor energy metabolism in photoreceptors to understand its relationship to maintenance and viability of the retina.
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|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:|
|Hurley, James B (2017) Warburg's vision. Elife 6:|
|Du, Jianhai; Rountree, Austin; Cleghorn, Whitney M et al. (2016) Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina. J Biol Chem 291:4698-710|
|Contreras, Laura; Ramirez, Laura; Du, Jianhai et al. (2016) Deficient glucose and glutamine metabolism in Aralar/AGC1/Slc25a12 knockout mice contributes to altered visual function. Mol Vis 22:1198-1212|
|Zhang, Lijuan; Du, Jianhai; Justus, Sally et al. (2016) Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest 126:4659-4673|
|Du, Jianhai; Yanagida, Aya; Knight, Kaitlen et al. (2016) Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. Proc Natl Acad Sci U S A 113:14710-14715|
|Hurley, James B; Lindsay, Kenneth J; Du, Jianhai (2015) Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res 93:1079-92|
|Hurley, James B; Chao, Jennifer R (2015) It's never too late to save a photoreceptor. J Clin Invest 125:3424-6|
|Carroll, Patrick A; Diolaiti, Daniel; McFerrin, Lisa et al. (2015) Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27:271-85|
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