Dataset Information

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

ABSTRACT: Photoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle, and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine, and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

SUBMITTER: Li B

PROVIDER: S-EPMC7644940 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Li Bo B Zhang Ting T Liu Wei W Wang Yekai Y Xu Rong R Zeng Shaoxue S Zhang Rui R Zhu Siyan S Gillies Mark C MC Zhu Ling L Du Jianhai J

iScience 20201014 11

Photoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have ...[more]

PMID: 33196018

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Project description:BackgroundIn inherited retinal disorders such as retinitis pigmentosa (RP), rod photoreceptor-specific mutations cause primary rod degeneration that is followed by secondary cone death and loss of high-acuity vision. Mechanistic studies of retinal degeneration are challenging because of retinal heterogeneity. Moreover, the detection of early cone responses to rod death is especially difficult due to the paucity of cones in the retina. To resolve heterogeneity in the degenerating retina and investigate events in both types of photoreceptors during primary rod degeneration, we utilized droplet-based single-cell RNA sequencing in an RP mouse model, rd10.ResultsUsing trajectory analysis, we defined two consecutive phases of rod degeneration at P21, characterized by the early transient upregulation of Egr1 and the later induction of Cebpd. EGR1 was the transcription factor most significantly associated with the promoters of differentially regulated genes in Egr1-positive rods in silico. Silencing Egr1 affected the expression levels of two of these genes in vitro. Degenerating rods exhibited changes associated with metabolism, neuroprotection, and modifications to synapses and microtubules. Egr1 was also the most strongly upregulated transcript in cones. Its upregulation in cones accompanied potential early respiratory dysfunction and changes in signaling pathways. The expression pattern of EGR1 in the retina was dynamic during degeneration, with a transient increase of EGR1 immunoreactivity in both rods and cones during the early stages of their degenerative processes.ConclusionOur results identify early and late changes in degenerating rd10 rod photoreceptors and reveal early responses to rod degeneration in cones not expressing the disease-causing mutation, pointing to mechanisms relevant for secondary cone degeneration. In addition, our data implicate EGR1 as a potential key regulator of early degenerative events in rods and cones, providing a potential broad target for modulating photoreceptor degeneration.

Project description:Vertebrate rods and cones operate over a wide range of ambient illumination, which is provided by light adaptation mechanisms regulating the sensitivity and speed of the phototransduction cascade. Three calcium-sensitive feedback loops are well established in both rods and cones: acceleration of the quenching of a light-activated visual pigment and cGMP synthesis by guanylate cyclase, and increased affinity of ion channels for cGMP. Accumulating evidence suggests that the molecular mechanisms of light adaptation are more complex. While investigating these putative mechanisms, we discovered a novel phenomenon, observing that the recovery of light sensitivity in rods after turning off non-saturating adaptive light can take tens of seconds. Moreover, after a formal return of the membrane current to the dark level, cell sensitivity to the stimuli remains decreased for a further 1-2 min. We termed this phenomenon of prolonged photoreceptor desensitization 'adaptation memory' (of previous illumination) and the current study is focused on its detailed investigation in rods and an attempt to find the same phenomenon in cones. In rods, we have explored the dependencies of this phenomenon on adapting conditions, specifically, the intensity and duration of adapting illumination. Additionally, we report that fish and frog red-sensitive cones possess similar features of adaptation memory, such as a drop in sensitivity just after the steps of bright light and slow sensitivity recovery. However, we have found that the rate of this process and its nature are not the same as in rods. Our results indicate that the nature of the temporary drop in the sensitivity in rods and cones after adapting steps of light is different. In the rods, adaptation memory could be attributed to the existence of long-lasting modifications of the components of the phototransduction cascade after adapting illumination. In cones, the observed form of the adaptation memory seems to be due to the sensitivity drop caused by a decrease in the availability of the visual pigment, that is, by bleaching.

Dataset Information

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

Publications

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

Similar Datasets

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