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Erika Tatiana Camacho, Danielle Brager, Ghizlane Elachouri, Tatyana Korneyeva, Geraldine Millet-Puel, Jose Alain Sahel, Thierry D Leveillard; Modeling Cone Aerobic Glycolysis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):567.
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© ARVO (1962-2015); The Authors (2016-present)
Patients affected by the inherited retinal disease retinitis pigmentosa (RP), experience loss ofvision due to photoreceptor degeneration of the rods followed by the cones, leading to irreversible blindness. Photoreceptors rely on aerobic glycolysis to supply the metabolites necessary for outer segment renewal and maintenance. In this work, we develop a mathematical model to investigate the biochemical processes in the cones triggered by glucose catabolism and by Rod-derived cone viability factor (RdCVF), in order to better understand the mediated survival exerted by the rods on the cones.
Utilizing differential equations, we develop a nonlinear system of enzymatic functions to mathematically model both molecular interactions in a cone and cellular interactions of the photoreceptors. At the molecular level, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aerobic glycolysis. We model three phases of glucose catabolism and their interplay: aerobic glycolysis, oxidative phosphorylation (OXPHO), and the pentose phosphate pathway (PPP). We incorporated the dominant divergence of pyruvate into OXPHO and the creation of ROS through the leakage in the mitochondrial respiratory chain. We also included the detoxification of ROS that results from the production of nicotinamide adenine dinucleotide phosphate (NADPH) through the PPP. We considered the partition of the carbon flux between glycolysis and the PPP as well as glycolysis and the Kennedy pathway. At the cellular level the model takes into account the supplied neuroprotective factors, growth factors, and nutrients mediated by the retinal pigment epithelium (RPE), the competition between the rods and cones for these resources, as well as the photoreceptors energy uptake and consumption.
Analysis and simulation of the mathematical model confirm the cone-on-rod reliance. We narrowed our focus on the carbohydrate metabolism in the cones, which is accelerated due to the RdCVF secreted by the rods. We demonstrate via mathematical analysis the mediated effects ofRdCVF on cone survival, with regard to carbohydrate metabolism, antioxidant lipid synthesis,and energy production.
Our findings demonstrate the utility of a mathematical model of aerobic glycolysis for exploration of the roles of various pathways. Additionally, our model illustrates the relevance of quantitative models to fully understand the mechanisms driving cone death in RP.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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