Glycolytic reliance promotes anabolism in photoreceptors

Abstract

Sensory neurons capture information from the environment and convert it into signals that can greatly impact the survival of an organism. These systems are thus under heavy selective pressure, including for the most efficient use of energy to support their sensitivity and efficiency1. In this regard, the vertebrate photoreceptor cells face a dual challenge. They not only need to preserve their membrane excitability via ion pumps by ATP hydrolysis2 but also maintain a highly membrane rich organelle, the outer segment, which is the primary site of phototransduction, creating a considerable biosynthetic demand. How photoreceptors manage carbon allocation to balance their catabolic and anabolic demands is poorly understood. One metabolic feature of the retina is its ability to convert the majority of its glucose into lactate3,4 even in the presence of oxygen. This phenomenon, aerobic glycolysis, is found in cancer and proliferating cells, and is thought to promote biomass buildup to sustain proliferation5,6. The purpose of aerobic glycolysis in the retina, its relevance to photoreceptor physiology, and its regulation, are not understood. Here, we show that rod photoreceptors rely on glycolysis for their outer segment (OS) biogenesis. Genetic perturbations targeting allostery or key regulatory nodes in the glycolytic pathway impacted the OS size. Fibroblast growth factor (FGF) signaling was found to regulate glycolysis, with antagonism of this pathway resulting in anabolic deficits. These data demonstrate the cell autonomous role of the glycolytic pathway in OS maintenance and provide evidence that aerobic glycolysis is part of a metabolic program that supports the biosynthetic needs of a normal neuronal cell type.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…Graymore first noted that photoreceptors might be the site of LDHA expression in the retina (Graymore, 1964). Since then many groups have noted the high expression of LDHA in the retina and specifically in photoreceptors, in a pattern matching the expression of PKM2 (Chinchore et al, 2017; Casson et al, 2016; Rueda et al, 2016). …”

“…Photoreceptors express high levels of enzyme isoforms that favor the conversion of pyruvate into lactate, including hexokinase II (HKII), the pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase subunit A, LDHA (Aït-Ali et al, 2015; Chinchore et al, 2017; Casson et al, 2016 Lindsay et al, 2014; Rajala et al, 2016; Reidel et al, 2011). Hexokinase catalyzes the first reaction of glycolysis via the phosphorylation of glucose.…”

“…This enzyme is also preferentially expressed in rapidly dividing cells including cancer cells. While some controversy exists regarding the expression of PKM1 in photoreceptors, with some reporting the absence of PKM1 and others observing it (Chinchore et al, 2017; Casson et al, 2016; Lindsay et al, 2014; Rajala et al, 2016; Rueda et al, 2016), PKM2 is indisputably the dominant isoform in photoreceptors.…”

“…Rajala et al observed PI3K-mediate phosphorylation of PKM2 with light stimulation, leading to enzyme inhibition, suggesting a reduced production of pyruvate with light and potentially a build-up of glycolytic intermediates leading to anabolic reactions (Rajala et al, 2016). Chinchore et al have recently shown that impairing glycolysis specifically in rods with a variety of methods (interfering with the activity of LDHA, PFK, and PK) leads to shorter rod outer segments (OS), which is thought to be the result of reduced OS synthesis (Chinchore et al, 2017). Their data suggest that high glycolytic flux and the production of lactate is necessary for the biosynthesis of OS.…”

“…Interestingly, while reducing PKM2 led to shorter OS, overexpression of PKM1 had a similar effect. The observation that OS are shorter with both reduced glycolytic flux and increased flux suggests that the ability of the photoreceptor to precisely regulate the glycolytic rate is crucial to the OS length (Chinchore et al, 2017). Supporting the hypothesis that glycolytic intermediates are needed for biosynthesis during light exposure, keeping animals with impaired glycolytic function in the dark rescued OS length (Chinchore et al, 2017).…”