Autophagy activation and photoreceptor survival in retinal detachment

Xiao, Jianhui; Yao, Jingyu; Ji, Lin; Ferguson, T.; Weber, Sarah R.; Sundstrom, Jeffrey M.; Wubben, Thomas J.; Besirli, Cagri G.; Zacks, David N.

doi:10.1016/j.exer.2021.108492

Cited by 9 publications

(2 citation statements)

References 45 publications

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“…Our data failed to demonstrate any increased expression of glycolytic enzymes during experimental detachment. In fact, there was a generalised downregulation of glycolytic machinery, and a striking loss of HK2, a response also documented by others (Weh et al, 2020;Xiao et al, 2021). The failure to upregulate glycolytic machinery most likely reflects limited availability of glucose.…”

Section: Discussionsupporting

confidence: 64%

Investigations into photoreceptor energy metabolism during experimental retinal detachment

Chidlow

Chan

Wood

et al. 2022

Front. Cell. Neurosci.

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Retinal detachment is a sight-threatening disorder, which occurs when the photoreceptors are separated from their vascular supply. The aim of the present study was to shed light on photoreceptor energy metabolism during experimental detachment in rats. Retinal detachment was induced in the eyes of rats via subretinal injection of sodium hyaluronate. Initially, we investigated whether detachment caused hypoxia within photoreceptors, as evaluated by the exogenous and endogenous biomarkers pimonidazole and HIF-1α, as well as by qPCR analysis of HIF target genes. The results showed no unequivocal staining for pimonidazole or HIF-1α within any detached retina, nor upregulation of HIF target genes, suggesting that any reduction in pO2 is of insufficient magnitude to produce hypoxia-induced covalent protein adducts or HIF-1α stabilisation. Subsequently, we analysed expression of cellular bioenergetic enzymes in photoreceptors during detachment. We documented loss of mitochondrial, and downregulation of glycolytic enzymes during detachment, indicating that photoreceptors have reduced energetic requirements and/or capacity. Given that detachment did not cause widespread hypoxia, but did result in downregulated expression of bioenergetic enzymes, we hypothesised that substrate insufficiency may be critical in terms of pathogenesis, and that boosting metabolic inputs may preserve photoreceptor bioenergetic production and, protect against their degeneration. Thus, we tested whether supplementation with the bioavailable energy substrate pyruvate mitigated rod and cone injury and degeneration. Despite protecting photoreceptors in culture from nutrient deprivation, pyruvate failed to protect against apoptotic death of rods, loss of cone opsins, and loss of inner segment mitochondria, in situ, when evaluated at 3 days after detachment. The regimen was also ineffective against cumulative photoreceptor deconstruction and degeneration when evaluated after 4 weeks. Retinal metabolism, particularly the bioenergetic profiles and pathological responses of the various cellular subtypes still presents a considerable knowledge gap that has important clinical consequences. While our data do not support the use of pyruvate supplementation as a means of protecting detached photoreceptors, they do provide a foundation and motivation for future research in this area.

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Section: Discussionsupporting

confidence: 64%

Investigations into photoreceptor energy metabolism during experimental retinal detachment

Chidlow

Chan

Wood

et al. 2022

Front. Cell. Neurosci.

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“…Due to the importance of bioenergetics in all aspects of cell function and maintenance of various components of the eye, there is a critical need for methods to study its regulation. In particular, neural retina and RPE depend on metabolism for both generation of energy as well as intra- and inter-cellular signaling 14 , 15 , 16 , 17 . Because of their high oxidative capacity, isolated tissues of the eye are not well-maintained under static conditions 18 , 19 and therefore study of isolated components of the eye require flow systems that can both maintain and assess metabolic processes.…”

Section: Discussionmentioning

confidence: 99%

Maintaining and Assessing Various Tissue and Cell Types of the Eye Using a Novel Pumpless Fluidics System

Grumbine,

Kamat,

Bao

et al. 2023

JoVE

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Many in vitro models used to investigate tissue function and cell biology require a flow of media to provide adequate oxygenation and optimal cell conditions required for the maintenance of function and viability. Toward this end, we have developed a multi-channel flow culture system to maintain tissue and cells in culture and continuously assess function and viability by either in-line sensors and/or collection of outflow fractions. The system combines 8-channel, continuous optical sensing of oxygen consumption rate with a built-in fraction collector to simultaneously measure production rates of metabolites and hormone secretion. Although it is able to maintain and assess a wide range of tissue and cell models, including islets, muscle, and hypothalamus, here we describe its operating principles and the experimental preparations/protocols that we have used to investigate bioenergetic regulation of isolated mouse retina, mouse retinal pigment epithelium (RPE)-choroid-sclera, and cultured human RPE cells. Innovations in the design of the system, such as pumpless fluid flow, have produced a greatly simplified operation of a multi-channel flow system. Videos and images are shown that illustrate how to assemble, prepare the instrument for an experiment, and load the different tissue/cell models into the perifusion chambers. In addition, guidelines for selecting conditions for protocol- and tissue-specific experiments are delineated and discussed, including setting the correct flow rate to tissue ratio to obtain consistent and stable culture conditions and accurate determinations of consumption and production rates. The combination of optimal tissue maintenance and real-time assessment of multiple parameters yields highly informative data sets that will have great utility for research in the physiology of the eye and drug discovery for the treatment of impaired vision.

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The Expression of Parthanatos Markers and miR-7 Mimic Protects Photoreceptors from Parthanatos by Repressing α-Synuclein in Retinal Detachment

Gao

Wang

Lü

et al. 2023

The American Journal of Pathology

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Autophagy activation and photoreceptor survival in retinal detachment

Cited by 9 publications

References 45 publications

Investigations into photoreceptor energy metabolism during experimental retinal detachment

Investigations into photoreceptor energy metabolism during experimental retinal detachment

Maintaining and Assessing Various Tissue and Cell Types of the Eye Using a Novel Pumpless Fluidics System

The Expression of Parthanatos Markers and miR-7 Mimic Protects Photoreceptors from Parthanatos by Repressing α-Synuclein in Retinal Detachment

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