Disturbed mitochondrial function restricts glutamate uptake in the human Müller glia cell line, MIO-M1

Vohra, Rupali; Gurubaran, Iswariyaraja Sridevi; Henriksen, Ulla; Bergersen, Linda Hildegard; Rasmussen, Lene Juel; Desler, Claus; Skytt, Dorte M.; Kolko, Miriam

doi:10.1016/j.mito.2017.02.003

Cited by 19 publications

(14 citation statements)

References 25 publications

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“…In general, glucose deprivation has been shown to boost mitochondrial activity in Müller cells, suggesting a shift from glycolytic metabolism to mitochondrial oxidative phosphorylation during metabolic stress. 10,11 Since glucose deprivation combined with GPR81 agonist treatment resulted in increased mitochondrial function, it is tempting to suggest that GPR81 activation compensatorily increases metabolism of available metabolites to meet the energy requirements. Moreover, previous studies have identified that silencing of GPR81 in cultured pancreatic carcinoma cells led to a 50% reduction in mitochondrial activity within 24 hours, 19 further emphasizing that GPR81 is crucial in maintaining mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

“…13,40,41 However, the cells may subside to mitochondrial energy production during accumulative stress to potentially sustain the gradientdriven transport of glutamate by indirectly maintaining the sodium-potassium pump. 11 Nevertheless, the dual role of lactate as a metabolite and signaling molecule by GPR81 activation has revealed novel regulatory features of lactate, in which GPR81 activation is able to boost mitochondrial metabolism and function, ultimately leading to maintained survival of Müller cells. In summary, the present study reveals novel properties of lactate as an active metabolic energy substrate and as a regulatory molecule that activates GPR81 receptors in primary Müller cells.…”

Section: Discussionmentioning

confidence: 99%

“…2,4,5 Previous studies have suggested that Müller cells are predominantly glycolytic [6][7][8] but shift to mitochondrial metabolism during excessive stress, such as sparse glucose availability and accumulation of reactive oxygen species (ROS). [9][10][11] With this in mind, lactate should be crucial during physiological conditions in the retina since retinal lactate is produced at a higher rate than pyruvate as the end product of glycolysis. Moreover, retinal tissue expresses high amounts of various monocarboxylate transporters (MCTs), which facilitate lactate uptake.…”

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confidence: 99%

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Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Vohra

Aldana

Bergersen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Vohra R, Aldana BI, Waagepetersen H, Bergersen LH, Kolko M. Dual properties of lactate in Müller cells: the effect of GPR81 activation. Invest Ophthalmol Vis Sci. 2019;60:999-1008. https://doi.org/ 10.1167/iovs.18-25458PURPOSE. Besides being actively metabolized, lactate may also function as a signaling molecule by activation of the G-protein-coupled receptor 81 (GPR81). Thus, we aimed to characterize the metabolic effects of GPR81 activation in Müller cells.METHOD. Primary Müller cells from mice were treated with and without 10 mM L-lactate in the presence or absence of 6 mM glucose. The effects of lactate receptor GPR81 activation were evaluated by the addition of 5 mM 3,5-DHBA (3,5-dihydroxybenzoic acid), a GPR81 agonist. Western blot analyses were used to determine protein expression of GPR81. Cell survival was assessed through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assays. Lactate release was quantified by commercially available lactate kits. 13 Clabeling studies via mass spectroscopy and Seahorse analyses were performed to evaluate metabolism of lactate and glucose, and mitochondrial function. Finally, Müller cell function was evaluated by measuring glutamate uptake.RESULTS. The lactate receptor, GPR81, was upregulated during glucose deprivation. Treatment with a GPR81 agonist did not affect Müller cell survival. However, GPR81 activation diminished lactate release allowing lactate to be metabolized intracellularly. Furthermore, GPR81 activation increased metabolism of glucose and mitochondrial function. Finally, maximal glutamate uptake decreased in response to GPR81 activation during glucose deprivation.CONCLUSIONS. The present study revealed dual properties of lactate via functioning as an active metabolic energy substrate and a regulatory molecule by activation of the GPR81 receptor in primary Müller cells. Thus, combinational therapy of lactate and GPR81 agonists may be of future interest in maintaining Müller cell survival, ultimately leading to increased resistance toward retinal neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Vohra

Aldana

Bergersen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…; Inman & Harun‐Or‐Rashid ; Vohra et al. , ; Vohra & Kolko ). The most common energy source, glucose, is essential for the first step of energy metabolism, glycolysis.…”

Section: Introductionmentioning

confidence: 99%

Potential metabolic markers in glaucoma and their regulation in response to hypoxia

Vohra

Dalgaard

Vibæk

et al. 2019

Acta Ophthalmologica

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Purpose: To assess novel differences in serum levels of glucose, lactate and amino acids in patients with normal-tension glaucoma (NTG) compared to agematched controls, at baseline and in response to universal hypoxia. Methods: Twelve patients diagnosed with NTG and eleven control subjects underwent normobaric hypoxia for 2 hr. Peripheral venous blood samples were taken at baseline, during hypoxia and in the recovery phase. Serum glucose and lactate levels were measured by a blood gas analyser. Amino acids were analysed by high-performance liquid chromatography. Results: Baseline levels of lactate and total amino acids were significantly lower in patients with NTG compared to healthy controls. No differences were seen in blood glucose levels between the two groups. Lactate levels remained unchanged during hypoxia in the control group, but increased in patients with NTG. In the recovery phase, total amino acid levels were reduced in the control group, whereas no changes were found in patients with NTG. Conclusion: Reduced serum levels of lactate and total amino acids were identified as potential markers for NTG. Moreover, significant differential regulatory patterns of certain amino acids were found in patients with NTG compared to control subjects. Overall, our results suggest a link between systemic energy metabolites and NTG and support a novel understanding of glaucoma as an inner retinal manifestation of a systemic condition.

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“…36 Another study, however, showed that mitochondria are important for Müller glial function and disturbing mitochondria reduced glutamate uptake and cell survival. 37 We have found that both glycolysis and mitochondrial respiration were active in Müller glia. QMMuC-1 and PMC had similar levels of glycolysis and glycolytic capacity.…”

Section: Discussionmentioning

confidence: 97%

Characterization of a Spontaneously Immortalized Murine Müller Glial Cell Line QMMuC-1

Augustine

Pavlou

O’Hare

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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RESULTS.Immunocytochemistry showed that QMMuC-1 express known Müller glial markers, including glutamine synthetase, glial fibrillary acidic protein (GFAP), alpha-smooth muscle actin (a-SMA), Aquaporin 4, Kir4.1, interleukin 33 (IL-33), and sex determining region Y (SRY)-box2 (Sox2), but not Cone arrestin, Calbindin 1, CD68, and ionized calcium-binding adapter molecule 1 (Iba1). Compared with PMC, QMMuC-1 express higher levels of chemokine (C-C motif) ligand 2 (Ccl2), VEGFA, and glutamate aspartate transporter (GLAST), but lower levels of interleukin 6 (IL-6), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF1), and neurotrophin 3 (NTF3). Whole-cell patch clamp recordings demonstrated characteristic inward currents in response to L-glutamate and L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) by QMMuC-1 cells. The L-glutamate-induced current was significantly higher in QMMuC-1 cells compared with PMC. Bioenergetic profiling studies revealed similar levels of glycolysis and basal mitochondrial respiration between QMMuC-1 and PMC. However, mitochondrial spare capacity was significantly lower in QMMuC-1 compared with PMC. CONCLUSIONS.Our results suggest that the QMMuC-1 Müller glial cell line retains key characteristics of PMC with its unique profiles in cytokine/neurotrophic factor expression and mitochondrial respiration. QMMuC-1 has utility as an invaluable tool for understanding the role of Müller glia in physiological and pathological conditions.

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Disturbed mitochondrial function restricts glutamate uptake in the human Müller glia cell line, MIO-M1

Cited by 19 publications

References 25 publications

Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Potential metabolic markers in glaucoma and their regulation in response to hypoxia

Characterization of a Spontaneously Immortalized Murine Müller Glial Cell Line QMMuC-1

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