Quantitative modeling of rod outer segment phagocytosis and recycling.

There is continual turnover of macromolecules as part of maintenance. This allows removal of damaged macromolecules and their replacement. A prime example is the turnover of the rod photoreceptor outer segment. Every day, 10% of rod photoreceptor outer segments is phagocytosed by the neighboring retinal pigment epithelium cells where they undergo phagolysosomal degradation. For example, the proteins are broken down to their component amino acids. These components need to be efficiently recycled back to the rod photoreceptor, while the damaged components can be eliminated. These damaged molecules need to be replaced either by synthesis or from the circulation. Here, we calculate the demand fluxes for the different turnover processes relevant for outer segment phagocytosis. We show that the breakdown of proteins poses a potential osmotic problem. We develop computational models of rhodopsin digestion and recycling, which show that the duration of phagocytosis, digestion, and recycling of molecular components occur on a just in time basis. These findings imply that even modest impairments in lysosomal function, changes in protein abundances of key degradative enzymes or metabolite transporters could disrupt this fine-tuned process with potential consequences for photoreceptor survival.