Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

Joyal, Jean‐Sébastien; Gantner, Marin L.; Smith, Lois E.H.

doi:10.1016/j.preteyeres.2017.11.002

Cited by 120 publications

(123 citation statements)

References 390 publications

(520 reference statements)

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“…Low α-ketoglutarate levels promote the stabilization of hypoxiainducible factor 1α (HIF-1α) and secretion of VEGF-A, leading to macular neovascularization. 6 Thus consistent with previous suggestions, dysregulation of glucose metabolism, particularly in TCA cycles, may be a driving force in AMD and other retinal disease pathogenesis, but the underlying mechanisms require further exploration. 6,37,38 The decrease in glutamine levels in AH in AMD participants was unsurprising, given that published articles on AMD metabolomics demonstrate higher plasma levels of glutamine in early AMD 39 and lower levels in intermediate AMD.…”

Section: Discussionsupporting

confidence: 86%

“…6 Thus consistent with previous suggestions, dysregulation of glucose metabolism, particularly in TCA cycles, may be a driving force in AMD and other retinal disease pathogenesis, but the underlying mechanisms require further exploration. 6,37,38 The decrease in glutamine levels in AH in AMD participants was unsurprising, given that published articles on AMD metabolomics demonstrate higher plasma levels of glutamine in early AMD 39 and lower levels in intermediate AMD. 29 However, Hu et al 40 proposed that the lens may be involved in contributing compounds to the AH, thereby maintaining glutamine homeostasis in ischemia and reperfusion models.…”

Section: Discussionsupporting

confidence: 86%

“…6 Another possible mechanism may include the normal retinal pigment epithelium (RPE) cells that have a high rate of reductive carboxylation, whereby the glutamine enters the TCA with generation of citrate, displaying a higher K/C ratio for fatty acid biosynthesis. 6,44 In AMD, the ageing and apoptosis of RPE cells, leading to a disrupted redox balance and impairment of fatty acid synthesis, 6,45 are possibly correlated with the decreases in reductive glutamine use, showing lower levels of K/C. However, this hypothesis still needs to be validated from animal models with isotope labeled experiments or further clinical trials.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration

Han

Wei

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose Energy compromise underpins wet age-related macular degeneration (wAMD) pathogenesis, but the relationship between glucose metabolism and the disease remains unclear. Here, we characterized aqueous humor (AH) to elucidate glucose-related metabolic signatures in patients with wAMD. Methods In total, 25 eyes of 25 patients with wAMD were divided into phakic (15 eyes), pseudophakic (10 eyes), and intravitreal injections of ranibizumab (13 eyes) wAMD groups. Twenty patients with cataract (21 eyes) served as controls. Ultrahigh-performance liquid chromatography tandem mass spectrometry was used to quantitatively characterize AH. Results Twenty-one metabolites related to glucose metabolism were identified in AH from 45 patients. Tricarboxylic acid (TCA)-related metabolic substrates, including citrate, were detected in AH and were significantly increased in AMD ( P < 0.01) and AMD pseudophakic groups ( P < 0.05). In contrast, α -ketoglutarate levels were decreased in the AMD group ( P < 0.05). The α -ketoglutarate/citrate ratio was significantly decreased, corresponding to 71.71% and 93.6% decreases in the AMD (phakic and pseudophakic) groups as compared with controls ( P < 0.001), revealing a significant positive correlation with glutamine. A lower mean glutamine and higher glutamate level were detected in AMD cases compared with controls. No significant differences were observed for lactic acid or other Krebs cycle metabolites. Intravitreal injection significantly alleviated mean central foveal thickness but did not significantly alter metabolites. Conclusions Compromised glucose TCA cycle and altered glutamine metabolism are implicated in the AH metabolism in wAMD. These findings highlight potential treatments for alleviating wAMD from a metabolic perspective.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration

Han

Wei

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…It has been shown that the risk of neuronal cell death is constant, regardless of the underlying cause [23].…”

Section: Introductionmentioning

confidence: 99%

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Vélez

Vijayalakshmi

et al. 2019

Preprint

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One Sentence Summary: The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. Abstract: 244Main Text: 9,039References: 83 AbstractNeurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death.Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

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“…Dietary modulation of the lipid supply can positively influence diseases with pathological neovascularization such as ROP, AMD, and DR in patients and in animal models of retinopathy (Gong et al , ). Photoreceptor energy demands drive vessel growth (Sapieha, ; Joyal et al , , ; Fu et al , ), while photoreceptor‐derived oxidative stress and inflammation lead to retinal vascular damage or regression (Kern & Berkowitz, ; Sun et al , ). Retinal disorders such as ROP, DR, AMD, RP, and Zellweger spectrum disorder (ZSSD) are associated with disturbances in photoreceptor activity, which may further affect the blood supply and induce pathological vascular remodeling during disease progression.…”

Section: Dyslipidemia In Neurovascular Retinopathiesmentioning

confidence: 99%

Dyslipidemia in retinal metabolic disorders

Chen

Cagnone

et al. 2019

EMBO Mol Med

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The light‐sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid‐rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.

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Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

Cited by 120 publications

References 390 publications

Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration

Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Dyslipidemia in retinal metabolic disorders

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