Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa
Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang
Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang
Published February 12, 2025
Citation Information: J Clin Invest. 2025;135(7):e185796. https://doi.org/10.1172/JCI185796.
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Research Article Metabolism Ophthalmology

Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa

Abstract

Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, noncell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.

Authors

Salvatore Marco Caruso, Xuan Cui, Brian M. Robbings, Noah Heaps, Aykut Demirkol, Bruna Lopes Da Costa, Daniel T. Hass, Peter M.J. Quinn, Jianhai Du, James B. Hurley, Stephen H. Tsang

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Figure 2

VHL ablation in photoreceptors results in glycolytic reprogramming and robust transcriptional remodeling.

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VHL ablation in photoreceptors results in glycolytic reprogramming and r...
VHL ablation resulted in a robust transcriptional remodeling of photoreceptor behavior, altering several biological processes, including the regulation of metabolic processes, cellular responses to hypoxia, and ATP generation. (A) Volcano plot of DESeq2 results comparing VHL ablated (Vhl–/–; Pde6bH620Q/H620Q; Pde6gCre–ERT2/+, n = 4) and unablated (VhlloxP/loxP; Pde6bH620Q/H620Q; Pde6gCre–ERT2/+, n = 4) neuroretina identified a variety of DEGs, including glycolytic intermediates such as Glut1, Hk1, Pkm, and Ldha. (B) Heatmap of significant DEGs identified a wide range of targets both up and down regulated following intervention. (C) Gene ontology analysis (GO) performed on DEGs identified a wide range of biological processes implicated in the knockout including glycolysis, hypoxia responses, and ATP synthesis (D) Schematic of glycolysis pathway and enzymes associated with each reaction. (E) DEGs demonstrating upregulation of glycolysis and TCA cycle as identified by RNA-seq analysis at 3 weeks of age comparing VHL ablated and unablated mice. Statistics were performed in DESeq2 using Wald tests and multiple comparisons were accounted for using the Benjamini-Hochberg method to control the FDR.