Mitochondrial pyruvate transport in retinal health and disease

PROJECT SUMMARY/ABSTRACT The retina is the most metabolically active neuronal tissue in the human body. The defect in the energy metabolism of photoreceptor neurons and their supporting cells including glia and retinal pigment epithelium (RPE), emerges as an important underlying cause for retinal degenerative

diseases such as inherited retinal degeneration and aging-related macular degeneration (AMD). Previous studies and data from our lab support that photoreceptors, glial cells, and RPE are biochemically adapted to form a metabolic ecosystem: 1) RPE transports glucose from choroid blood supply to photoreceptors; 2) Photoreceptors metabolize most of the glucose into lactate; 3)

Lactate inhibits glycolysis in RPE to facilitate glucose transport; 4) Lactate stimulate Müller glia to synthesize glutamine for photoreceptors. The long term goal of this project is to define the metabolic interactions between photoreceptors and Müller glia and between RPE and outer retina in vivo and identify their roles in retinal function and degeneration.

Mitochondrial pyruvate carrier (MPC) controls the entry of pyruvate from glycolysis into mitochondria for oxidative metabolism. We recently found that the deletion of MPC in the retina depletes glutamine and glutamate, inhibits glutamine utilization and enhancing ketone body oxidation, resulting in a progressive decline of visual function and retinal degeneration. Our

preliminary data showed that the deletion of MPC in photoreceptors causes much milder phenotype than whole retina knockout, supporting the metabolic interaction that lactate is utilized by other cells. The objective of this proposal is to investigate the roles of mitochondrial pyruvate transport in photoreceptor, Müller cells and RPE in metabolic interactions, visual function, and

retinal survival. We plan to conditionally knockout MPC in photoreceptors, glia or RPE separately and rigorously test our hypothesis using advanced tracer methodology, mass spectrometry, in vivo infusion with 13C tracers, high-resolution imaging of metabolites, visual function tests, optical coherence tomography, and transmission electron microscopy.

The outcome of this research will establish a conceptual framework for retinal metabolism that describes how glucose is transported and utilized in different retinal cells and describes how disruption of metabolism in one kind of retinal cells impacts the metabolism, function, and viability of other retinal cells. This new knowledge will provide the basis for understanding the

mechanisms of retinal degenerative diseases and lay the foundation for developing new treatments.