Control of Photoreceptor Metabolism

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DESCRIPTION (provided by applicant): Photoreceptors are among the most metabolically active cells. They have extraordinarily large mitochondria and consume oxygen at exceptional rates. Energy production by glycolysis and oxidative phosphorylation must keep pace with energy consumption in these highly specialized neurons. Photoreceptors consume oxygen slightly faster in darkness than in light, but the processes that consume energy are qualitatively very different. Mutations that create an imbalance of energy production and consumption under specific conditions may introduce stresses that cause oxidative damage and cell death. The aim of this proposal is to establish a quantitative model to understand production and consumption of energy in photoreceptors. Specific aim 1 is to develop methods to quantify the rates at which various biochemical reactions consume high energy metabolites in photoreceptors. In specific Aim 2 we will use those methods, together with specific genetic mutations in mice, to investigate the processes in photoreceptors that produce and consume energy. In aim 2 we also will determine how energy production is regulated. Specific aim 3 focuses on the role that the calcium-binding protein, recoverin, plays in energy metabolism. Understanding how energy is produced and consumed in these highly metabolic neurons will provide information fundamental to understanding photoreceptor function. These studies also will provide much-needed insights into why specific classes of inherited mutations cause stress and retinal disease.