Photoreceptors are different from neurons in the brain because they are exposed to electromagnetic radiation from the environment. Membranes with the most accumulated exposure to radiation are shed from the tip of the photoreceptor outer segment and replaced by addition of newly synthesized membranes at the base of the outer segment. This type of anabolic activity occurs daily. The high demand for anabolic metabolism during these periods of renewal is reminiscent of the metabolic demands of cancer cells. Recent findings in cancer research have identified important metabolic adaptations of cancer cells that enhance their growth. Specific biochemical mechanisms divert glycolytic intermediates away from energy production and instead into anabolic pathways that support growth. Cancer cells carry out aerobic glycolysis, prefer glutamine as a fuel for their mitochondria and they express a unique form of pyruvate kinase, PKM2 that can be regulated by tyrosine phosphorylation. By reducing PKM2 activity cancer cells divert glycolytic intermediates away from energy production to more anabolic roles like phospholipid synthesis. We have carried out preliminary studies that suggest photoreceptors use some of the same types of adaptations that cancer cells use to enhance their anabolic activity. The goal of this project is to extend discoveries from cancer metabolism research toward an understanding of photoreceptor metabolism. We will explore the novel hypothesis that photoreceptor cells regulate anabolic activity by mechanisms similar to those used by cancer cells. The outcome of this project will be a framework with which to understand how energy metabolism influences photoreceptor function and survival.
Photoreceptors require anabolic metabolism to support daily renewal of membranes that compensates for damage caused by exposure to electromagnetic radiation. Recent findings have revealed specific biochemical mechanisms that have been adapted by cancer cells to enhance anabolic activity. Our preliminary studies indicate that photoreceptors and cancer cells use similar mechanisms to enhance anabolic activity. Findings from our studies may expedite the understanding of the underlying causes of retinal disease and provide a framework for understanding what photoreceptors require to stay alive and to function.
|Du, Jianhai; Linton, Jonathan D; Hurley, James B (2015) Probing Metabolism in the Intact Retina Using Stable Isotope Tracers. Methods Enzymol 561:149-70|
|Hurley, James B; Lindsay, Kenneth J; Du, Jianhai (2015) Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res 93:1079-92|
|Lindsay, Ken J; Du, Jianhai; Sloat, Stephanie R et al. (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc Natl Acad Sci U S A 111:15579-84|
|Du, Jianhai; Cleghorn, Whitney; Contreras, Laura et al. (2013) Cytosolic reducing power preserves glutamate in retina. Proc Natl Acad Sci U S A 110:18501-6|