Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa
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
Affiliations
San Joon Lee
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Department of Ophthalmology, Kosin University College of Medicine, #262 Gamcheon-ro, Seo-gu, Busan 49267, Korea
Douglas Emery
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Eric Vukmanic
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Yekai Wang
Departments of Ophthalmology and Visual Sciences and Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA
Xiaoqin Lu
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Wei Wang
Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Enzo Fortuny
Department of Neurosurgery, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Robert James
Department of Neurosurgery, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Henry J. Kaplan
Department of Ophthalmology, St. Louis University School of Medicine, St. Louis MO 63110, USA
Yongqing Liu
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Jianhai Du
Departments of Ophthalmology and Visual Sciences and Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA; Corresponding author
Douglas C. Dean
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Corresponding author
Summary: 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.
