**The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration**

### **Tirthankar Sinha** †**, Larissa Ikelle** †**, Muna I. Naash \* and Muayyad R. Al-Ubaidi \***

Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA; tsinha2@Central.UH.EDU (T.S.); likelle@Central.UH.EDU (L.I.)


† These authors contributed equally to this work.

Received: 4 February 2020; Accepted: 6 March 2020; Published: 10 March 2020

**Abstract:** In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid–ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argumen<sup>t</sup> for the exploration of serine-based clinical interventions for retinal pathologies.

**Keywords:** serine; retinal degeneration; diabetic retinopathy; macular degeneration; macular telangiectasia; oxidative stress; sphingolipids; retina; RPE; Müller cells

### **1. Why Is Serine Important to the Entire Retina?**

Serine is a non-essential amino acid directly involved in cellular homeostasis, proliferation, and di fferentiation [1,2]. The cells of the neural retina are no exception, and, in fact, exhibit a grea<sup>t</sup> dependence on serine and its exhaustive variety of metabolic intermediates [3]. Serine uptake occurs either by delivery from the bloodstream or it can be synthesized by the anabolism of the glycolytic intermediate, 3-phosphoglycerate (3-PG) [4] in the retina (neural retina-RPE, Figure 1). After uptake or synthesis, serine becomes available and serves as a central node in many cellular processes [5].


**Figure 1.** Pathway depicting serine biosynthesis from glycolysis. Metabolic intermediates involved in the enzymatic synthesis of L-serine from glycolysis is shown here with the rate limiting step marked with a dashed grey arrow. The enzymes involved in respective steps are shown in bold italics below the arrow for the individual reaction.

Other than being an integral amino acid in multiple essential proteins, free serine is essential for generating cysteine, glycine, methionine, and sphingolipids [5]. Glycine and cysteine are essential intermediates. Glycine is a precursor molecule for porphyrins and purine nucleotides [6]. Cysteine on the other hand is important in the protection of neuronal cells and for the production of taurine [7]. Together they form glutathione (GSH), a critical anti-oxidant in the retina [8]. Sphingolipids are elemental components of the phospholipid bilayer and are indispensable to cellular viability, homeostasis and function [2,3,5]. Furthermore, serine derived-metabolites have proven essential to methylation [2], apoptosis, and synaptic receptor activation [6].

The integrality of serine to cellular function has been appreciated by dysregulatory events appearing in many retinopathies. Reduced serine levels have been implicated in the etiology of macular related diseases such as macular telangiectasia type 2 (Mac Tel), age related macular degeneration, and diabetic retinopathy (DR) [9,10]. The retina is a complex stratified tissue consisting of the retinal pigment epithelium (RPE), a critical layer of cells for retinal homeostasis, and the neural retina containing the two types of photoreceptor cells. The neural retina also harbors the second order neurons and the retinal ganglion cells (RGC) that form the optic nerve. Serine proves to be a vital intermediate in many of these processes. Consequently, our goal is to provide a focused review of the role of serine homeostasis in maintaining optimum retinal function and proper oxidative balance.

### **2. Why Does the Retina Need to Synthesize Serine?**

In most tissues, serine uptake from either blood or proteolysis su fficiently meets cellular metabolic requirements. However, there are tissues that mandate an elevated level of serine and, accordingly, upregulate enzymes for serine biosynthesis. As previously highlighted, this biosynthetic pathway (Figure 1) helps in maintaining the redox potential of the cell [11]. The primary source of serine biosynthesis is glucose [12], which in most cells is utilized via glycolysis. Serine biosynthesis branches from one of the glycolytic intermediates, 3-phosphoglycerate. The rate limiting step for serine biosynthesis is the reaction involving phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate into phosphoserine. This is followed by the removal of the phosphate to generate l-serine.

It has been previously shown that the retina expresses high levels of all enzymes involved in serine biosynthesis. However, the RPE appears to express even higher levels than the neural retina [13] as has been shown by flux studies, whereby the RPE readily converts glucose into serine [10,14]. Further experiments verified that the neural retina possess an e fficient system for serine uptake. [15].

### *De Novo Serine Synthesis in Müller Cells*

Transport of serine, a neutral amino acid, across the tight blood–retinal barrier into the RPE or across the endothelial cells and to the neural retina is supposedly inadequate [16]. So the retina increases the levels of intracellular serine through de novo synthesis [12]. Further supply of serine to photoreceptors and the inner retina is provided by the RPE and retinal Müller cells [15]. The latter was demonstrated by co-immunofluorescence with anti-PHGDH and anti-cellular retinaldehyde–binding protein (CRALBP) antibodies showing that the serine de novo synthesis pathway is indeed present in the Müller cells [17]. Since serine metabolism is central to maintaining redox and oxidative balance, ion flux, glutamate levels, and many other support functions [18], Müller cells through their de novo synthesis of serine play major roles in these functions [17].

Many retinopathies are associated with loss of Müller glia [17]. Mac Tel, is a pathology of the retina recently characterized by significant reductions in serine synthesis and loss of central vision [16]. Although the macula (anatomic) is a small cone-dense region of the retina occupying only 1.4% of the total area of the retina, it harbors approximately 8% of the total cone population and 60% of all RGCs [19]. The macula is incredibly metabolically active and relies heavily on Müller glia [18]. Not only has localization of serine synthesis in the neural retina been demonstrated in Müller cells, but relative to peripheral Müller cells, those of the macula seem to show increased expression of PHGDH [10]. Moreover, the macular Müller cells show increased GSH and glycine production and are more susceptible to induced stress [10].

### **3. Serine Homeostasis Plays an Important Role in the Maintenance of the Retina**
