Abstract
Patients affected by retinitis pigmentosa, an inherited retinal disease, experience a decline in vision due to photoreceptor degeneration leading to irreversible blindness. Rod-derived cone viability factor (RdCVF) is the most promising mutation-independent treatment today. To identify pathologic processes leading to secondary cone photoreceptor dysfunction triggering central vision loss of these patients, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aerobic glycolysis. We develop a nonlinear system of enzymatic functions and differential equations to mathematically model molecular and cellular interactions in a cone. We use uncertainty and sensitivity analysis to identify processes that have the largest effect on the system and their timeframes. We consider the case of a healthy cone, a cone with low levels of glucose, and a cone with low and no RdCVF. The three key processes identified are metabolism of fructose-1,6-bisphosphate, production of glycerol-3-phosphate and competition that rods exert on cone resources. The first two processes are proportional to the partition of the carbon flux between glycolysis and the pentose phosphate pathway or the Kennedy pathway, respectively. The last process is the rods’ competition for glucose, which may explain why rods also provide the RdCVF signal to compensate.
Highlights
When photoreceptor degeneration occurs, rod and cone OS begin to shorten as a result of disruptions in the renewal and underlying metabolic processes
There is a partitioning in the cone photoreceptors between glucose going through aerobic glycolysis for cone OS renewal and glucose going through oxidative phosphorylation (OXPHO), the main adenosine triphosphate (ATP) production step
rod-derived cone viability factor (RdCVF) stimulates glucose going through aerobic glycolysis, while reactive oxygen species (ROS) favors glucose leading to the production of carbon dioxide (CO2) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), CO2 + NADPH, through the phosphate pathway (PPP) and inhibits both glucose flowing through aerobic glycolysis and OXPHO
Summary
Rod and cone OS begin to shorten as a result of disruptions in the renewal and underlying metabolic processes. These disruptions, if magnified, can lead to eventual death of the photoreceptors. We model explicitly the mode of action of RdCVF and glucose uptake with the goal of understanding the key mechanisms that drive cone OS renewal in a healthy retina so that these conclusions may guide experimental work and identify key processes. The purpose of this study is to mathematically analyze the molecular and cellular level interactions that occur in a non-diseased retina with the goal of gaining insight into an understanding of photoreceptor vitality so that our findings may contribute to the development of therapies that can stop cone photoreceptor degeneration
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