Metabolic Features of Mouse and Human Retinas: Rods versus Cones, Macula versus Periphery, Retina versus RPE

Li, Bo; Zhang, Ting; Liu, Wei; Wang, Yekai; Xu, Rong; Zeng, Shaoxue; Zhang, Rui; Zhu, Siyan; Gillies, Mark C; Zhu, Ling; Du, Jianhai

doi:10.1016/j.isci.2020.101672

Cited by 41 publications

(53 citation statements)

References 61 publications

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“…As an example, consistent with studies in cancer cells, we found that Nrf2 significantly boosted several genes in the pentose phosphate pathway, including those for glucose-6-phosphate dehydrogenase ( G6pd ), transaldolase 1 ( Taldo1 ), and phosphogluconate dehydrogenase ( Pgd ) ( 60 ). A recent study of RPE metabolism found that the pentose phosphate pathway is of very high importance in the RPE/choroid relative to the retina ( 61 ). Nrf2’s ability to enhance throughput through a prominent pathway of the RPE, in addition to its more well-known effects on oxidative stress, suggests that it may provide additional benefits beyond those provided by an antioxidant.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

Wu¹,

Ji²,

Ivanchenko³

et al. 2021

JCI Insight

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Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2–treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).

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Section: Discussionmentioning

confidence: 99%

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

Wu¹,

Ji²,

Ivanchenko³

et al. 2021

JCI Insight

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“…P5C produces glutamate through a NAD-dependent P5C dehydrogenase (P5CDH), encoded by ALDH4A1 gene in the mitochondria. Glutamate, an important neurotransmitter in the retinal neurons, is also a precursor for glutamine, gamma-aminobutyric acid (GABA) and mitochondrial TCA cycle intermediates (Li et al 2020 ). Glutamate can convert into αKG to enter the TCA cycle through either glutamate dehydrogenase or transaminases such as aspartate transaminase (AST), alanine transaminase (ALT), and phosphoserine aminotransferase (PSAT).…”

Section: Proline Catabolism Synthesis and Transport In Rpementioning

confidence: 99%

“…Fourth, proline is an important nitrogen source. Our recent studies show that both human and mouse retinal explants preferentially uptake glutamate and aspartate, whereas proline could generate and release these amino acids to be used by the retina (Chao et al 2017 ; Li et al 2020 ). Glutamine is a common precursor for glutamate and aspartate; however, glutamine catabolism can also produce toxic free ammonia.…”

Section: Proline Metabolism In Retinal Healthmentioning

confidence: 99%

“…Vertebrate retinas are light-sensitive neuronal tissues with large metabolic demands for phototransduction, maintenance of ion gradients, and biosynthesis of daily-shed photoreceptor outer segments (Hurley et al 2015 ). Due to the absence of a direct blood supply, photoreceptors must absorb nutrients, including glucose, amino acids, fatty acids, ketone bodies and vitamins through the retinal pigment epithelium (RPE) (Du et al 2013 ; Hurley et al 2015 ; Li et al 2020 ). The RPE consists of a monolayer of polarized epithelial cells that transports metabolites between the choroidal blood supply and the outer retina.…”

Section: Introductionmentioning

confidence: 99%

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Proline metabolism and transport in retinal health and disease

Zhu

Lim

et al. 2021

Amino Acids

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The retina is one of the most energy-demanding tissues in the human body. Photoreceptors in the outer retina rely on nutrient support from the neighboring retinal pigment epithelium (RPE), a monolayer of epithelial cells that separate the retina and choroidal blood supply. RPE dysfunction or cell death can result in photoreceptor degeneration, leading to blindness in retinal degenerative diseases including some inherited retinal degenerations and age-related macular degeneration (AMD). In addition to having ready access to rich nutrients from blood, the RPE is also supplied with lactate from adjacent photoreceptors. Moreover, RPE can phagocytose lipid-rich outer segments for degradation and recycling on a daily basis. Recent studies show RPE cells prefer proline as a major metabolic substrate, and they are highly enriched for the proline transporter, SLC6A20. In contrast, dysfunctional or poorly differentiated RPE fails to utilize proline. RPE uses proline to fuel mitochondrial metabolism, synthesize amino acids, build the extracellular matrix, fight against oxidative stress, and sustain differentiation. Remarkably, the neural retina rarely imports proline directly, but it uptakes and utilizes intermediates and amino acids derived from proline catabolism in the RPE. Mutations of genes in proline metabolism are associated with retinal degenerative diseases, and proline supplementation is reported to improve RPE-initiated vision loss. This review will cover proline metabolism in RPE and highlight the importance of proline transport and utilization in maintaining retinal metabolism and health.

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“…Metabolites generated in all these conditions can in turn reflect on the composition of structures in close contact with the retina, such as the lens and the vitreous [ 20 ], which are both largely acellular and have little metabolic activity per se [ 21 ]. As such, few attempts at characterizing the metabolic profile of retina, vitreous and lens have been made [ 22 , 23 , 24 , 25 , 26 , 27 ], some of which in relation to systemic pathological conditions [ 26 , 27 ]. However, to the best of our knowledge the impact of IRDs on eye metabolism has only marginally been addressed [ 17 , 28 ], and a correlation among metabolomes in retina and vitreous/lens has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Analysis of Vitreous/Lens and Retina in Wild Type and Retinal Degeneration Mice

Murenu

Kostidis

Lahiri

et al. 2021

IJMS

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Photoreceptors are the light‐sensing cells of the retina and the major cell type affected in most inherited retinal degenerations. Different metabolic pathways sustain their high energetic demand in physiological conditions, particularly aerobic glycolysis. The principal metabolome of the mature retina has been studied, but only limited information is available on metabolic adaptations in response to key developmental events, such as eye opening. Moreover, dynamic metabolic changes due to retinal degeneration are not well understood. Here, we aimed to explore and map the ocular metabolic dynamics induced by eye opening in healthy (wild type) or Pde6b‐mutant (retinal degeneration 1, Rd1) mice, in which photoreceptors degenerate shortly after eye opening. To unravel metabolic differences emerging before and after eye opening under physiological and pathophysiological conditions, we performed nuclear magnetic resonance (NMR) spectroscopy‐based metabolome analysis of wild type and Rd1 retina and vitreous/lens. We show that eye opening is accompanied by changes in the concentration of selected metabolites in the retina and by alterations in the vitreous/lens composition only in the retinal degeneration context. As such, we identify NAcetylaspartate as a potential novel vitreous/lens marker reflecting progressive retinal degeneration. Thus, our data can help elucidating mechanisms underlying key events in retinal physiology and reveal changes occurring in pathology, while highlighting the importance of the vitreous/lens in the characterization of retinal diseases.

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Metabolic Features of Mouse and Human Retinas: Rods versus Cones, Macula versus Periphery, Retina versus RPE

Abstract: Besides glucose, mouse and human retinas heavily consume aspartate and glutamate Mature retinal organoids robustly consume aspartate and glutamate Cone-rich retinas and the neural macula use more pyruvate Neural retinas and RPE differ in their metabolite uptake and release

Cited by 41 publications

References 61 publications

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

Proline metabolism and transport in retinal health and disease

Metabolic Analysis of Vitreous/Lens and Retina in Wild Type and Retinal Degeneration Mice

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