Review
Müller Cell Metabolic Signatures: Evolutionary Conservation and Disruption in Disease

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Highlights

  • Müller cells are the primary macroglia of the retina, that have a highly conserved metabolic signature across species.

  • During degeneration, Müller cells’ metabolic signatures diverge and become chaotic.

  • The glutamate cycle is disrupted during retinal degeneration, leading to levels of glutamate and glutamine varying irrespective of glutamine synthetase levels.

  • Factors contributing to Müller cell metabolic homogeneity in health and heterogeneity in disease are currently matters of speculation requiring further investigation.

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.

Introduction

The retina is a thin, multilaminar extension of the central nervous system (CNS) located at the back of the eye. This neural tissue is responsible for the detection and initial processing of visual primitives including luminance, contrast, direction, and velocity before sending them through the optic nerve to other areas of CNS for further processing. The retina is highly organized and compact and, like the rest of CNS, comprises neurons and glia. The largest population of glia in the retina, and the only retina-specific glia, is the Müller cell (Box 1). This review focuses on the metabolism of Müller cells, which are found in every vertebrate retina described to date, and features retinas from multiple vertebrate species (both healthy and diseased) and characterizes them based on their metabolic phenotype. Metabolic phenotyping, put simply, describes an analysis of combinations of small molecules and proteins allowing the characterization of unique cell classes (Box 2). Müller cells have a remarkably stable and homogeneous metabolic phenotype in healthy retinas across vertebrate species, indicating high levels of conservation through evolution. However, this stability becomes chaotic in retinal disease. While the regulatory mechanisms responsible for this homogeneity in Müller cells across the retina and what specific alterations lead to the loss of this homogeneity in disease are not understood, the metabolic precision can be measured and is an area of active exploration. Identifying precipitating factors leading to metabolic changes in disease, and what impact these changes have on the ability of Müller cells to support neuronal function, not only has significance in understanding the progression of retinal disease but will also be fundamental in designing therapeutics compatible with the diseased retina.

Section snippets

Retinal Function and Metabolic Support

Retinal neurons can be broadly split into outer and inner retinal neurons based on retinal stratification. Photoreceptors, found in the outer retinal layers, are highly specialized neurons responsible for the initial detection of light and the transduction of that signal to the first synapse in visual processing. Signals are then propagated from photoreceptors to the inner retinal neurons, which are responsible for the shaping and refinement of the visual primitives before they are transmitted

Müller Cells and the Glutamate Cycle

Glutamate is a nonessential amino acid central to numerous metabolic and neurotransmitter processes in cells [5., 6., 7.]. In the nervous system, glutamate is the most common excitatory neurotransmitter [8,9]. Glutamate is also a precursor for the synthesis of GABA, the most prevalent inhibitory neurotransmitter [10,11]. Although the signaling by glutamate as a neurotransmitter is often the most referenced function in the nervous system, it is important to recognize that glutamate plays a

Müller Cells and Taurine

Müller cells are responsible for regulating their surrounding microenvironment, including the osmolarity of the extracellular space. In large part this is done through the rapid removal of released neurotransmitters and K+ from the extracellular space [4]. In the healthy retina, Müller cells also regulate their own cell volume closely and do not swell in response to neurotransmitter release the way neurons do. This is, in part, due to the transmembrane transport of taurine and release by Müller

Müller Cell Metabolic Signatures in Disease

Müller cells have a remarkably consistent small-molecule metabolic profile that is constant across all Müller cells in the retina across species [40., 41., 42.]. Healthy Müller cells have a profile composed of high taurine (>10 mM), medium to high glutamine (0.3–1.0 mM), medium to low glutamate (~0.1–0.5 mM), and medium levels of GS [43]. However, this is not to say that there are no species differences in Müller cell metabolism. GABA transport by Müller cells has been observed only in mammals[

Müller Cell Glutamate Pathways in Degenerated Tissue

The global increases in glutamine occurring coincidentally with the loss of GS is a perplexing phenomenon warranting further examination of glutamate metabolism in Müller cells. Previous suggestions that Müller cell glutamate transport fails early in retinal degeneration [28,55]. It has been previously hypothesized that the decrease in GS is related to a loss of EAAT1, the main glutamate transporter found on Müller cells [56,57]. In this model of metabolic changes in Müller cells in response to

Concluding Remarks

The loss of a unified metabolic phenotype in Müller cells in response to widespread photoreceptor death is not in and of itself particularly remarkable. Müller cells are well preserved in the evolutionary record, with the same general signature and function being observed across the animal kingdom, from avians to reptiles and mammals. One would expect cells that are substantially similar in terms of metabolic signatures, morphological and physiological function across almost 300 million years

Acknowledgments

This work was supported by the National Institutes of Health (RO1 EY015128, RO1 EY028927, P30 EY014800) and an Unrestricted Research Grant from Research to Prevent Blindness, New York, NY to the Department of Ophthalmology and Visual Sciences, University of Utah.

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