**8. Concluding Remarks**

Serine metabolism has vast interconnectivity with many of the homeostatic mechanisms that work in concert to maintain retinal health and function, as depicted in Figure 3. As reviewed above, considerable evidence has indicated that both the RPE and Müller cells of the inner retina have the requisite enzymes for serine biosynthesis. Besides the significant contribution of these two tissues to the serine pool of the entire retina, we also established the role de novo serine synthesis plays in redox currency generation and in mitigating free radical stress for both the neural retina and RPE. Given the retina is a metabolically high functioning tissue with high-energy demands and recent advancements indicating extra-mitochondrial contribution to the elevated presence of free radicals compared to other tissues, it calls for such extensive measures. Thus we show that while the pentose phosphate pathway might be sufficient to maintain the redox balance for other tissues, the retina depends upon additional tools, which it obtains primarily from serine metabolism: like NADPH from de novo biosynthesis, glycine, GSH and NADH. In addition, a review of the literature on serine-based lipid derivatives like phosphatidylserine, sphingolipids, and their toxic form, i.e., ceramides, helped us conclude the essential role these play in both RPE phagocytosis and membrane integrity in retinal homeostasis, while their imbalance is a critical factor in inherited retinal dystrophies. Coupled with the above observations and the recent advance on using D-serine as therapeutic candidate for diabetic retinopathy, we further postulate that there are a multitude of potential therapies targeting serine metabolism that hold tremendous promise against retinal diseases. We highlighted the prospect of using PHGDH replacement gene therapy or serine supplement therapy for Mac Tel patients and serine racemase and ceramide synthase inhibition for DR patients. Careful evaluation of recent literature also helped us align with the growing consensus that metabolic vulnerabilities add an extra layer of susceptibility for IRD patients. Thus, boosting serine biosynthesis and serine metabolism by pharmacological activators or complimentary gene therapy in these patients may reduce this risk factor and help postpone their onset of degeneration. Consequently, and in this review, our goal was to delineate some of the important roles of serine and demonstrate how they are imperative to the health of the retina. By providing a comprehensive view of the relationship between serine and retinal health, we hope to bring more awareness to the importance of serine to the retina so it can be further assessed for treatment options, and proteins that mediate its metabolic processes can be considered as viable targets for gene therapy.

**Figure 3.** Graphical summary of serine metabolism in the retina. Serine homeostasis is primarily maintained by the RPE and retinal glia. The RPE transports and generates serine, which is ultimately transported to the photoreceptors. Additionally, important serine metabolic products such as glycine and cysteine are transported or catabolized to be used as fuel, as the energetic requirements of the RPE are very high. Photoreceptors also receive serine from the Müller glia and astrocytes. Glial cells are vital to the macula and generate serine from glycolysis, which is crucial in maintaining the redox balance in the photoreceptors, controlling neurotransmission, and mediating inflammation response elements. (IS, inner segment; OS, outer segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer).

**Funding:** This study was supported by a gran<sup>t</sup> from the National Eye Institute (EY026499) to MIN and MRA. **Conflicts of Interest:** The authors declare no conflict of interest.
