Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

San Joon Lee, Douglas Emery, Eric Vukmanic, Yekai Wang, Xiaoqin Lu, Wei Wang, Enzo Fortuny, Robert James, Henry J Kaplan, Yongqing Liu, Jianhai Du, Douglas C Dean. Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa. Cell reports. 2023 Aug 31;42(9):113054

PMID: 37656622

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