Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration
Lijuan Zhang, … , James B. Hurley, Stephen H. Tsang
Lijuan Zhang, … , James B. Hurley, Stephen H. Tsang
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4659-4673. https://doi.org/10.1172/JCI86905.
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Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Abstract

Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy–mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.

Authors

Lijuan Zhang, Jianhai Du, Sally Justus, Chun-Wei Hsu, Luis Bonet-Ponce, Wen-Hsuan Wu, Yi-Ting Tsai, Wei-Pu Wu, Yading Jia, Jimmy K. Duong, Vinit B. Mahajan, Chyuan-Sheng Lin, Shuang Wang, James B. Hurley, Stephen H. Tsang

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Figure 7

Sirt6 knockout accelerates the flow of carbons from glucose to downstream metabolites.

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Sirt6 knockout accelerates the flow of carbons from glucose to downstre...
(A) Schematic representation of glycolysis and the TCA cycle, highlighting key metabolic intermediates that are compared between groups in B. Red font indicates incorporation of the 13C isotope into the downstream metabolites evaluated by GC-MS. (B) The ratio of 13C enrichment of each metabolite at 3 and 4 weeks is shown. At 3 weeks, Sirt6–/–Pde6bH620Q/H620Q mice have significantly higher levels of 13C-labeled metabolites compared with controls. At 4 weeks, the significance remained for only some metabolites: pyruvate, citrate, glutamine, and lactate. Gray dots and light red triangles represent values from individual Sirt6loxP/loxPPde6bH620Q/H620Q and Sirt6–/–Pde6bH620Q/H620Q mice, respectively. Black dots and red triangles represent the mean. –, Sirt6–/–Pde6bH620Q/H620Q mice; +, Sirt6loxP/loxPPde6bH620Q/H620Q mice. Two-tailed t tests were used for analysis. P < 0.001 for all metabolites at 3 weeks. P < 0.05 for pyruvate, citrate, glutamine, and lactate at 4 weeks. P = NS for other metabolites. n = 4 for Sirt6–/–Pde6bH620Q/H620Q and Sirt6loxP/loxPPde6bH620Q/H620Q mice at 3 and 4 weeks. (C and D) Metabolic relative abundance (fold change) of glycolytic and TCA cycle intermediates was assessed at 3 weeks of age. All metabolites were significantly upregulated in the treated group. Similar results were obtained at 4 weeks but with diminished significance. Three weeks, all metabolites: P < 0.001; n = 4 for both groups. 4 weeks, lactate: P = 0.009; pyruvate: P = 0.005; glutamine: P = 0.02; malate: P = 0.03; fumarate: P = 0.04; aspartate: P = 0.03; all others: P > 0.05. n = 4 for both groups. (E) LC-MS (without 13C labeling) revealed 11 significantly increased downstream metabolites in the Sirt6–/–Pde6bH620Q/H620Q retinae at 3 weeks of age. Two-tailed t tests were used for analysis. P < 0.05 for all metabolites; n = 6 per group.