Metabolic Coupling in the Aging Retina

An interesting perspective is presented in this open access paper, a discussion of the age-related decline in coupling of metabolism between different cell types in the retina. Cell metabolism cannot be considered in isolation for a given cell or cell type, particularly in the central nervous system, where, for example, supporting cells provide metabolites to neurons. As is the case for many aspects of aging, it is hard to draw clear lines of cause and effect between more fundamental forms of cell and tissue damage and downstream disruption of complex systems such as this within our biology.

One particular metabolic pathway of interest in various cell types is the process of Warburg glycolysis. This process was originally discovered in the 1920s by Otto Warburg, who made observations about large quantities of lactate production in the neuroretinal and tumor cells in the presence of oxygen. This usually occurs as part of an "organized duet" between two compartmentalized cell types. Traditional thinking has taught that one half of this duo, cells rich in glycolytic pathways, results in the end product of pyruvate. Subsequent fate ordinarily depends on the presence of oxygen and mitochondria; however, in certain cell types - including cancer cells, neurons, and photoreceptors - pyruvate is converted to lactate by lactate dehydrogenase. This abundance of lactate generated by these specialized cells feeds other supporting cells that have adapted to use lactate as a fuel source and NAD+ to support glycolysis.

Until recently, lactate was thought of as mainly a metabolic waste product, but its roles as a carbon source and energy substrate have slowly been uncovered in the past decade. The other half of this coupling phenomenon, oxidative phosphorylation, is responsible for energy production in various cells that act in a supportive manner to the more glycolytic cell types. One particularly interesting coupling phenomena that has been extensively studied is the lactate shuttling that occurs between astrocytes and neurons. In this system, astrocytes sense activity at a neuronal synapse and, as a result, deliver the energy substrate lactate to surrounding neurons.

Retinitis pigmentosa is characterized by a dysregulation within the metabolic coupling of the retina, particularly between the glycolytic photoreceptors and the oxidative retinal pigment epithelium. This phenomenon of metabolic uncoupling is seen in both aging and retinal degenerative diseases, as well as across a variety of cell types in human biology. In this review, we explored metabolic coupling between various cell types in the retina, how retinal degenerations progress through the breakdown of this metabolic coupling, how aging mirrors the loss of coupling seen in the degenerative conditions, and lastly the development of strategies aimed at renormalizing the metabolic coupling between photoreceptors and retinal pigment epithelium cells as an imprecision medicine therapeutic avenue.


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