Müller Cell Metabolic Signatures: Evolutionary Conservation and Disruption in Disease

Abstract

Müller cells are glia that play important regulatory roles in retinal metabolism. These roles have been evolutionarily conserved across at least 300 million years. Müller cells have a tightly locked metabolic signature in the healthy retina, which rapidly degrades in response to insult and disease. This variation in metabolic signature occurs in a chaotic fashion, involving some central metabolic pathways. The cause of this divergence of Müller cells, from a single class with a unique metabolic signature to numerous separable metabolic classes, is currently unknown and illuminates potential alternative metabolic pathways that may be revealed in disease. Understanding the impacts of this heterogeneity on degenerate retinas and the implications for the metabolic support of surrounding neurons will be critical to long-term integration of retinal therapeutics for the restoration of visual perception following photoreceptor degeneration.

Keywords: Müller cell; computational metabolic profiling; glutamine synthetase; retinal degeneration; retinal metabolism.

Figure 1.. Retinal Glutamate Metabolic Pathway.

Red cell indicates GABAergic cell (amacrine or subset of horizontal cells). Blue cell indicates glutamatergic cells (bipolar cells or photoreceptors). Yellow central cell indicates Müller cell. Circles indicate transporters.

Figure 2.. Müller Cell Metabolic Variability.

Müller cells represented by rectangles; color signifies metabolic class and changing colors indicate metabolic changes. Circles and ovals indicate retinal neurons (pink, photoreceptors; yellow, horizontal cells; blue, OFF-cone and rod bipolar cells; teal, ON-cone bipolar cells; red, GABAergic amacrine cells; purple, ganglion cells). Unfilled circles between cells indicate sign-inverting synapses. Filled circles indicate sign-conserving synapses. Bidirectional arrows indicate gap junctions. Irregular lines indicate neurite sprouting. Abbreviations: yy AC, GABAergic amacrine cell; G AC, glycinergic amacrine cell; BC, bipolar cell; HzC, horizontal cell; GC, ganglion cell.

Figure 3.. Potential Glutamate Metabolic Pathways in Retinal Degeneration.

Tan rectangle indicates the Müller cell boundaries, with brown box indicating mitochondria. Red markings indicate changes to the normal pathway uncovered by retinal degeneration and remodeling. (A) Reduction in glutamate transport by excitatory amino acid transporter 1 (EAAT1). (B) Increase in GDH pathway forming α-ketoglutarate. (C) Uncovering of another transaminase pathway in the absence of glutamine synthetase expression.

Figure I.. Pattern of n-Dimensional Images and Identification of Metabolic Signatures.

(A) Methodology for deriving metabolic signatures through image classification and separation of metabolic classes through k-mean Recognition cluster analysis. (B) 3D (TQE) metabolic profiles of Müller cells from three different mammalian species demonstrating similar relationships of amino acids across species.