Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery

Zhang, Ting; Zhu, Ling; Madigan, Michele C.; Liu, Wei; Shen, Weiyong; Cherepanoff, Svetlana; Zhou, Fanfan; Zeng, Shaoxue; Du, Jianhai; Gillies, Mark C

doi:10.7554/elife.43598

Cited by 38 publications

(35 citation statements)

References 38 publications

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“…7), in which the ring-shaped or disk-shaped distribution patterns of total carotenoids in each successive retinal layer shrink in diameter with increasing depth from the inner to the outer retina. These patterns are consistent with carotenoid localization within the Müller cell cone which terminates at the OLM, a hypothesis first advanced by Gass (41) and supported by studies on macular telangiectasia type 2 (MacTel) eyes in which Müller cell loss coincides with MP depletion and redistribution (42)(43)(44). We cannot rule out that the MP carotenoids are found in the foveal photoreceptor axons (Henle fibers) as well, especially since immunohistochemistry localizes GSTP1 and StARD3 to Henle fibers rather than Müller cells (19,21).…”

Section: Discussionsupporting

confidence: 83%

Imaging lutein and zeaxanthin in the human retina with confocal resonance Raman microscopy

George

Rognon

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Lutein and zeaxanthin are xanthophyll carotenoids that are highly concentrated in the human macula, where they protect the eye from oxidative damage and improve visual performance. Distinguishing lutein from zeaxanthin in images of the human retina in vivo or in donor eye tissues has been challenging because no available technology has been able to reliably differentiate between these two carotenoids, which differ only in the position of one C = C bond. Here, we report the differential distributions of lutein and zeaxanthin in human donor retinas mapped with confocal resonance Raman microscopy. Zeaxanthin is highly concentrated in the fovea, extending from the inner to the outer limiting membranes, with especially high concentrations in the outer plexiform layer, while lutein is much more diffuse at relatively lower concentration. Our results imply that zeaxanthin may play a more important role than lutein in human macular health and disease.

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Section: Discussionsupporting

confidence: 83%

Imaging lutein and zeaxanthin in the human retina with confocal resonance Raman microscopy

George

Rognon

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…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 efficient system for serine uptake.…”

Section: Why Is Serine Important To the Entire Retina?mentioning

confidence: 59%

“…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.…”

Section: De Novo Serine Synthesis In Müller Cellsmentioning

confidence: 99%

“…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].…”

Section: De Novo Serine Synthesis In Müller Cellsmentioning

confidence: 99%

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The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

Sinha

Ikelle

Naash

et al. 2020

Cells

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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.

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“…While the prevailing theory about MacTel pathogenesis currently posits that Muller cell dysfunction may be the primary cellular target [ 4 , 5 ], recent studies have shown that low serum serine levels are implicated in MacTel [ 26 ]. Serine is an important substrate in many metabolic pathways and its deficiency is associated with increased synthesis of atypical deoxysphingolipids, which are particularly toxic to neurons [ 26 , 27 , 28 , 29 ]. We postulate that an intact external limiting membrane on OCT with hyporeflective areas on AOSLO may be suggestive of early photoreceptor disruption (prior to Muller cell loss) as a consequence of serine deficiency.…”

Section: Discussionmentioning

confidence: 99%

Topographic Relationship between Telangiectasia and Cone Mosaic Disruption in Macular Telangiectasia Type 2

Zandi

Song

Micevych

et al. 2020

JCM

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In this cross-sectional observational study, we investigated the relationship between photoreceptor layer disruption and telangiectasia in patients diagnosed with early stage macular telangiectasia type 2 (MacTel). A total of 31 eyes (17 patients) with MacTel were imaged with adaptive optics scanning laser ophthalmoscopy (AOSLO) and optical coherence tomography angiography (OCTA). Confocal AOSLO was used to visualize dark regions of nonwaveguiding outer segments, which we refer to as “photoreceptor lesions”. En-face OCTA images of the deep capillary plexus (DCP) were used in conjunction with confocal AOSLO to evaluate the topographic relationship between areas of capillary telangiectasias and photoreceptor lesions. Among seven eyes with early stage MacTel (stage 0–2 based on OCT), we identified ten photoreceptor lesions, all of which were located within parafoveal quadrants containing DCP telangiectasia on OCTA. Seven of the lesions corresponded to the intact ellipsoid zone on spectral-domain OCT (SD-OCT), and three of these also corresponded to the intact interdigitation zone. This work demonstrates a topographic relationship between AOSLO photoreceptor lesions and DCP telangiectasias, and it also suggests that these lesions with normal SD-OCT appearance may represent areas of photoreceptors at risk for dysfunction. Thus, confocal AOSLO may have a meaningful role in detecting early photoreceptor abnormalities in eyes with MacTel.

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Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery

Cited by 38 publications

References 38 publications

Imaging lutein and zeaxanthin in the human retina with confocal resonance Raman microscopy

Imaging lutein and zeaxanthin in the human retina with confocal resonance Raman microscopy

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

Topographic Relationship between Telangiectasia and Cone Mosaic Disruption in Macular Telangiectasia Type 2

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