The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

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 argument for the exploration of serine-based clinical interventions for retinal pathologies.

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications

“…The PPP is critical for anabolic synthesis of macromolecules like ribose and the generation of nicotinamide adenine dinucleotide phosphate (NADPH), which is involved in combating oxidative stress. Serine biosynthesis in the retina was recently reviewed 56 and contributes to the synthesis of NADH/NADPH, sphingolipids, glutathione (GSH), and glycine. Importantly, macular telangiectasia type 2 and autosomal recessive retinitis pigmentosa have been genetically associated with disruptions in multiple steps of serine and glycine metabolism 57 – 59 .…”

“…6 ). The importance of these antioxidant enzymes in limiting oxidative damage has been comprehensively reviewed elsewhere 56 , 146 , 147 .

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“…Serine synthesis contributes to the production of serine, glycine, and cysteine, which are involved in the formation of GSH, along with anabolic macromolecules 150 . A recent review detailed the importance of serine metabolism in PR health 56 . Briefly, disruption of serine synthesis was found to significantly decrease FA synthesis, TCA intermediates, ATP production, and mitochondrial health 56 .…”

“…A recent review detailed the importance of serine metabolism in PR health 56 . Briefly, disruption of serine synthesis was found to significantly decrease FA synthesis, TCA intermediates, ATP production, and mitochondrial health 56 . These downstream metabolic effects may explain why many serine pathway mutations manifest as IRDs 56 , 151 .…”

Flavins Act as a Critical Liaison Between Metabolic Homeostasis and Oxidative Stress in the Retina

“…This has a cascade effect on cellular metabolism as multiple metabolic resources now need to be repurposed to facilitate the adequate supply of these three amino acids. As an example, glucose is partially shunted away from glycolysis into the serine biosynthesis pathway, which is then converted to glycine ( Sekhar et al, 2011 ; Lu, 2013 ; Panieri and Santoro, 2016 ; Sinha et al, 2020a , b ). The RPE already harbors an efficient serine biosynthesis pathway in physiological conditions that may be upregulated to support enhanced GSH requirements.…”