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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006641-28
Application #
8500280
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1986-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
28
Fiscal Year
2013
Total Cost
$360,983
Indirect Cost
$123,483
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
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
Adijanto, Jeffrey; Du, Jianhai; Moffat, Cynthia et al. (2014) The retinal pigment epithelium utilizes fatty acids for ketogenesis. J Biol Chem 289:20570-82
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
Du, Jianhai; Cleghorn, Whitney M; Contreras, Laura et al. (2013) Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina. J Biol Chem 288:36129-40
Chertov, Andrei O; Holzhausen, Lars; Kuok, Iok Teng et al. (2011) Roles of glucose in photoreceptor survival. J Biol Chem 286:34700-11
Linton, Jonathan D; Holzhausen, Lars C; Babai, Norbert et al. (2010) Flow of energy in the outer retina in darkness and in light. Proc Natl Acad Sci U S A 107:8599-604

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