Trends in Endocrinology & Metabolism
ReviewMüller Cell Metabolic Signatures: Evolutionary Conservation and Disruption in Disease
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.
References (88)
- et al.
Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease
Prog. Retin. Eye Res.
(2001) - et al.
γ-Aminobutyric acid in brain: its formation from glutamic acid
J. Biol. Chem.
(1950) - et al.
Metabolism and role of glutamate in mammalian brain
Prog. Neurobiol.
(1990) II. Glutamine and glutamate
Biomed. Pharmacother.
(2002)Cellular compartmentalization of carbonic anhydrase-C and glutamine synthetase in developing and mature mouse neural retina
Brain Res.
(1984)Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission
Cell
(1999)Glutaminases in brain: multiple isoforms for many purposes
Neurochem. Int.
(2015)GABA and glycine in synaptic vesicles: storage and transport characteristics
Neuron
(1991)High-density presynaptic transporters are required for glutamate removal from the first visual synapse
Neuron
(2006)- et al.
Glutamate in some retinal neurons is derived solely from glia
Neuroscience
(1994)
Evidence for a rate-limiting role of cysteinesulfinate decarboxylase activity in taurine biosynthesis in vivo
Comp. Biochem. Physiol. B
Taurine: the comeback of a neutraceutical in the prevention of retinal degenerations
Prog. Retin. Eye Res.
Structural organization of GABAergic circuitry in ectotherm retinas
Müller cell metabolic chaos during retinal degeneration
Exp. Eye Res.
Retinal remodeling in human retinitis pigmentosa
Exp. Eye Res.
Retinal remodeling and metabolic alterations in human AMD
Front. Cell. Neurosci.
Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS
Neurochem. Int.
Comparison between functional characteristics of healthy and pathological human retinal Müller glial cells
Surv. Ophthalmol.
Glia: much more than the neuron’s side-kick
Curr. Biol.
Gliotransmitters travel in time and space
Neuron
Glia–neuron interactions in the mammalian retina
Prog. Retin. Eye Res.
An immunocytochemical comparison of Müller cells and astrocytes in the cat retina
Exp. Eye Res.
The signature hypothesis: co-localizations of neuroactive substances as anatomical probes for circuitry analyses
Vis. Res.
The presence of three neuroactive peptides in putative glycinergic amacrine cells of an avian retina
Brain Res.
Functional neuroanatomy of the retina
Energy metabolism of rabbit retina as related to function: high cost of Na+ transport
J. Neurosci.
Müller cells in the healthy retina
The many roles of glutamate in metabolism
J. Ind. Microbiol. Biotechnol.
Glutamate: a truly functional amino acid
Amino Acids
The glutamate–glutamine (GABA) cycle: importance of late postnatal development and potential reciprocal interactions between biosynthesis and degradation
Front. Endocrinol.
Excitatory amino acid transmitters
Annu. Rev. Pharmacol. Toxicol.
Distribution of glutamine and glutamic acid in animal tissues
Biochem. J.
GABA and hippocampal inhibition
Br. J. Pharmacol.
Nitrogen control in bacteria
Microbiol. Rev.
Ammonium and glutamate released by neurons are signals regulating the nutritive function of a glial cell
J. Neurosci.
Transamination of amino acids in homogenates of rat brain
J. Neurochem.
Glutamate metabolic pathways and retinal function
J. Neurochem.
Glucose and synaptosomal glutamate metabolism: studies with [15N]glutamate
J. Neurochem.
Differential expression of three glutamate transporter subtypes in the rat retina
Cell Tissue Res.
Adenosinetriphosphate in glutamine synthesis
Nature
Müller cell localisation of glutamine synthetase in rat retina
Nature
Expression and function of glutamine transporters SN1 (SNAT3) and SN2 (SNAT5) in retinal Müller cells
Invest. Ophthalmol. Vis. Sci.
Ultrastructural demonstration of L-glutamate decarboxylase and cysteinesulfinic acid decarboxylase in rat retina by immunocytochemistry
Brain Res.
GABA and glutamate uptake and metabolism in retinal glial (Müller) cells
Front. Endocrinol.
Cited by (20)
Metabolic changes and retinal remodeling in Heterozygous CRX mutant cats (CRX<sup>RDY/+</sup>)
2023, Experimental Eye ResearchTNFAIP8 overexpression aggravates retinal pathophysiological features of diabetic retinopathy
2023, Experimental Eye ResearchProtective activity of tert-butylhydroquinone against oxidative stress and apoptosis induced by glutamate agonizts in R28 cells and mice retina
2022, Biomedicine and PharmacotherapyCitation Excerpt :Müller glial cells span nearly the entire thickness of the retina and wrap around retinal neurons, responsible for maintaining the homeostasis of the retina's extracellular environment (ions, neurotransmitter molecules, etc.) [15,16]. Müller cells support the survival of retinal neurons through the release of neurotrophic factors, the uptake and degradation of the excitotoxic glutamate, and the secretion of the antioxidant glutathione [17,18]. To explore whether tBHQ could promote the survival of RGCs by activating müller cells, we fluorescently stained müller cells with marker glutamine synthetase (Figs. 2A and 2B).
A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration
2020, Experimental Eye ResearchCitation Excerpt :The concentrations of the probed amino acids and proteins are used in the identification of cells beyond their morphology and synaptology (Table 1). For more in depth information on CMP technologies and usage see (Marc and Jones, 2002Marc et al., 1995; Pfeiffer et al., 2020a). Small molecule IgGs to GABA, L-glutamate, L-glutamine, glycine, and taurine, in addition to IgGs targeting glial fibrillary acidic protein (GFAP) were used in the classification of cells in the RPC1 volume.
p38 MAPK inhibitor SB202190 suppresses ferroptosis in the glutamate-induced retinal excitotoxicity glaucoma model
2024, Neural Regeneration Research