Metabolism in the Zebrafish Retina

Abstract

Retinal photoreceptors are amongst the most metabolically active cells in the body, consuming more glucose as a metabolic substrate than even the brain. This ensures that there is sufficient energy to establish and maintain photoreceptor functions during and after their differentiation. Such high dependence on glucose metabolism is conserved across vertebrates, including zebrafish from early larval through to adult retinal stages. As the zebrafish retina develops rapidly, reaching an adult-like structure by 72 hours post fertilisation, zebrafish larvae can be used to study metabolism not only during retinogenesis, but also in functionally mature retinae. The interplay between rod and cone photoreceptors and the neighbouring retinal pigment epithelium (RPE) cells establishes a metabolic ecosystem that provides essential control of their individual functions, overall maintaining healthy vision. The RPE facilitates efficient supply of glucose from the choroidal vasculature to the photoreceptors, which produce metabolic products that in turn fuel RPE metabolism. Many inherited retinal diseases (IRDs) result in photoreceptor degeneration, either directly arising from photoreceptor-specific mutations or secondary to RPE loss, leading to sight loss. Evidence from a number of vertebrate studies suggests that the imbalance of the metabolic ecosystem in the outer retina contributes to metabolic failure and disease pathogenesis. The use of larval zebrafish mutants with disease-specific mutations that mirror those seen in human patients allows us to uncover mechanisms of such dysregulation and disease pathology with progression from embryonic to adult stages, as well as providing a means of testing novel therapeutic approaches.

Differential Responses of Neural Retina Progenitor Populations to Chronic Hyperglycemia

“…In our diabetic model, we detected the most striking pathology within the photoreceptor layers, consisting of truncation of outer segments and cell loss. Photoreceptors are particularly susceptible to disturbances of glucose regulation due to their high metabolic activity and their primary use of glucose as an energy source [61]. In diabetes, altered expression or activity of glucose transporters can lead to an imbalance of energy supply and demand within the retina [62].…”

Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

“…The retina can be viewed as a metabolic ecosystem in which cells “share” nutrients and metabolites to sustain their function and health ( Kanow et al, 2017 ; Jaroszynska et al, 2021 ). Indeed, in the outer retina, rod and cone photoreceptors form an integrated network with the RPE, Müller glia, and with each other, and there is growing evidence that disruption of this ecosystem leads to metabolic failure, photoreceptor death and vision loss ( Jaroszynska et al, 2021 ).…”

“…The retina can be viewed as a metabolic ecosystem in which cells “share” nutrients and metabolites to sustain their function and health ( Kanow et al, 2017 ; Jaroszynska et al, 2021 ). Indeed, in the outer retina, rod and cone photoreceptors form an integrated network with the RPE, Müller glia, and with each other, and there is growing evidence that disruption of this ecosystem leads to metabolic failure, photoreceptor death and vision loss ( Jaroszynska et al, 2021 ). For instance, rods and Müller glia secrete large amounts of lactate as a glycolytic byproduct that is taken up by other cells as a metabolic fuel source, including by the RPE ( Winkler et al, 2004 ; Kanow et al, 2017 ; Jaroszynska et al, 2021 ).…”

“…Indeed, in the outer retina, rod and cone photoreceptors form an integrated network with the RPE, Müller glia, and with each other, and there is growing evidence that disruption of this ecosystem leads to metabolic failure, photoreceptor death and vision loss ( Jaroszynska et al, 2021 ). For instance, rods and Müller glia secrete large amounts of lactate as a glycolytic byproduct that is taken up by other cells as a metabolic fuel source, including by the RPE ( Winkler et al, 2004 ; Kanow et al, 2017 ; Jaroszynska et al, 2021 ). By taking up lactate, which is a carbon source for OXPHOS, glycolysis is suppressed in RPE cells, such that less glucose is used up and more can be transferred to photoreceptors ( Kanow et al, 2017 ).…”

“…Notably, given that 80% of glucose is metabolized by glycolysis, other carbon sources, such as lipids, including the long-chain fatty acid palmitate, are thought to fuel the TCA cycle in photoreceptor inner segments ( Joyal et al, 2016 ). Finally, photoreceptor mitochondria in the inner segment also regulate Ca 2+ ion homeostasis, regulating levels of this important cation to regulate membrane depolarization and neurotransmission ( Jaroszynska et al, 2021 ).…”