Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa
Ashley A. Rowe, … , Ruth Gordillo, Katherine J. Wert
Ashley A. Rowe, … , Ruth Gordillo, Katherine J. Wert
Published July 22, 2021
Citation Information: JCI Insight. 2021;6(17):e150898. https://doi.org/10.1172/jci.insight.150898.
View: Text | PDF
Research Article Metabolism Ophthalmology

Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa

Abstract

The metabolic environment is important for neuronal cells, such as photoreceptors. When photoreceptors undergo degeneration, as occurs during retinitis pigmentosa (RP), patients have progressive loss of vision that proceeds to full blindness. Currently, there are no available treatments for the majority of RP diseases. We performed metabolic profiling of the neural retina in a preclinical model of RP and found that TCA cycle intermediates were reduced during disease. We then determined that (a) promoting citrate production within the TCA cycle in retinal neurons during disease progression protected the photoreceptors from cell death and prolonged visual function, (b) supplementation with single metabolites within the TCA cycle provided this therapeutic effect in vivo over time, and (c) this therapeutic effect was not specific to a particular genetic mutation but had broad applicability for patients with RP and other retinal degenerative diseases. Overall, targeting TCA cycle activity in the neural retina promoted photoreceptor survival and visual function during neurodegenerative disease.

Authors

Ashley A. Rowe, Pinkal D. Patel, Ruth Gordillo, Katherine J. Wert

×

Figure 2

Supplementation with α-KG delays photoreceptor death, elevating citrate levels in the retina.

Options: View larger image (or click on image) Download as PowerPoint
Supplementation with α-KG delays photoreceptor death, elevating citrate ...
(A) Representative ERG traces for untreated (black) and α-KG–treated (red) arRP mice at a 2.5 log cd•s/m2 flash intensity. (B) Quantification of a-wave and (C) b-wave amplitudes shows a significant increase in visual response in arRP mice treated with α-KG, (D) which was not significant at 2 months for either the a-wave (E) or b-wave. (F) Representative ERG traces at a –1.1 log cd•s/m2 flash intensity. (G) Quantification of the b-wave amplitude shows a significant increase in visual response in arRP mice treated with α-KG, (H) which was not significant at 2 months. n ≥ 5 eyes. (I) Histology of arRP retinas untreated or treated with α-KG. Scale bar: 50 μm. (J) Morphometric quantification of ONL thickness spanning from the ONH. n = 3 eyes each group, with multiple counts per eye. Analyzed by multiple 2-tailed t tests with the Holm-Sidak method to correct for multiple comparisons. (K) Photopic ERG traces at a 3.1 log cd•s/m2 flash intensity. (L) Quantification of the peak amplitude for WT mice (purple), untreated arRP mice, and arRP mice treated with α-KG at 1 (M) and 2 months of age. n ≥ 5 eyes. Analyzed by 1-way ANOVA followed by Tukey’s multiple comparisons test. (N) Mass spectrometry for the relative abundance of TCA cycle intermediates in the retinas from untreated arRP mice and α-KG–treated arRP mice at 1 month of age. n ≥ 10 retinas. Scotopic ERG and mass spectrometry analyzed by student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01. α-KG, α-ketoglutarate; ERG, electroretinogram; arRP, autosomal recessive retinitis pigmentosa; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium; ONH, optic nerve head; TCA, tricarboxylic acid.