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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