Energy metabolism is essential for viability and function of retinas. Earlier studies of retinal metabolism revealed a predominance of aerobic glycolysis and higher rates of energy consumption in darkness than in light. New technologies have been developed since those pioneering studies. We're using mass spectrometry and other state-of-the- art techniques to investigate retinal energy metabolism in ways that were not possible in previous studies. Symbiotic metabolic relationships between neurons and glia are important for function and survival of neuronal tissues. In the retina photoreceptors die when Mller cells are ablated and the metabolic state of Mller cells changes when photoreceptors degenerate. One of the important functions of glia is to synthesize glutamine. In brain a metabolic cycle known as the Astrocyte Neuronal Lactate Shuttle explains the metabolic relationship between glia and neurons. However, the unusual morphology and metabolic requirements of the outer retina create unique metabolic requirements for photoreceptors and Mller cells. We have found evidence that aspartate produced by retinal neurons may play an important role in the relationship between neurons and Mller cells in retinas.
Our first aim i s to test the hypothesis that an aspartate/glutamine cycle shuttles carbons between neurons and Mller cells in retina. Metabolic demands of vertebrate retinas are different in darkness and in light. In darkness the demand for ATP is high as photoreceptors use it to fuel active ion pumps. In light, ATP demand is lower, but metabolites must be diverted for production of reducing power to fuel regeneration of rhodopsin and to synthesize phospholipids and other metabolic building blocks. During the previous funding period we made the novel observation that the metabolism of purine nucleotides is strongly influenced by illumination.
Our second aim i s to identify the mechanism by which purine metabolism is regulated by darkness and light. We will identify the mechanism by which darkness and light influence purine metabolism in retinas.

Public Health Relevance

Photoreceptors have unique metabolic requirements that change dramatically in darkness vs. in light. Findings from our studies will expedite the understanding of the underlying causes of retinal disease and provide a framework for understanding what photoreceptors require for viability and function.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Neuhold, Lisa
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University of Washington
Schools of Medicine
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Du, Jianhai; An, Jie; Linton, Jonathan D et al. (2018) How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration. Adv Exp Med Biol 1074:289-295
Rajala, Ammaji; Wang, Yuhong; Brush, Richard S et al. (2018) Pyruvate kinase M2 regulates photoreceptor structure, function, and viability. Cell Death Dis 9:240
Zhu, Siyan; Yam, Michelle; Wang, Yekai et al. (2018) Impact of euthanasia, dissection and postmortem delay on metabolic profile in mouse retina and RPE/choroid. Exp Eye Res 174:113-120
Chao, Jennifer R; Knight, Kaitlen; Engel, Abbi L et al. (2017) Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. J Biol Chem 292:12895-12905
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
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
Zhang, Lijuan; Du, Jianhai; Justus, Sally et al. (2016) Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest 126:4659-4673
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

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