Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

Vardjan, Nina; Chowdhury, Helena H.; Horvat, Anemari; Velebit, Jelena; Malnar, Maja; Muhič, Marko; Kreft, Marko; Krivec, Spela G.; Bobnar, Saša Trkov; Miš, Katarina; Pirkmajer, Sergej; Offermanns, Stefan; Henriksen, Gjermund; Storm‐Mathisen, Jon; Bergersen, Linda Hildegard; Zorec, Robert

doi:10.3389/fnmol.2018.00148

Cited by 64 publications

(82 citation statements)

References 67 publications

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“…Experiments were conducted with the addition of a bolus solution; 200 µl of extracellular solution containing NA was added by pipette to 200 µl of bath solution in the recording chamber. The application of a control bolus solution without reagents had no significant effect on the FRET signal, as reported previously 82,83 . Extracellular solution osmolality was 295-305 mOsm, measured with the Osmomat 030 freezing point osmometer (Gonotech GmbH, Germany).…”

supporting

confidence: 83%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca 2+ signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca 2+ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β 2-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of both upper and lower motor neurons in the brain and spinal cord, and by the progressive paralysis of voluntary muscles and death 1,2. The pathologic hallmark of ALS are cytoplasmic inclusions in motor neurons. In most cases (~95%) of sporadic and familial ALS, TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the key component of these inclusions 1-9. Moreover, TDP-43 has also been identified as the major protein in inclusions in frontotemporal dementia with ubiquitin-positive inclusions (FTD-U) 2,6. TDP-43 is a highly conserved protein (414 amino acids), ubiquitously expressed in all tissues and under physiological conditions, primarily localized to the nucleus; however, low levels are also present in the cytoplasm 2,3,8,10-13. TDP-43, an RNA-binding protein, is implicated in multiple aspects of RNA processing, including regulation of transcription, splicing, transport, and stabilization of mRNAs. It also regulates microRNA biogenesis and interacts with DNA. Therefore, its perturbance ...

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supporting

confidence: 83%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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“…The cells using lactic acid as their energy substrate need to transport extracellular lactic acid into the cell (8). Lactic acid function depends on the specific receptors, primarily monocarboxylic acid transporters (MCTs) and G protein-coupled receptors (GPR81) (20,21).…”

Section: Lactic Acid Receptorsmentioning

confidence: 99%

“…GPR81 is also known as hydroxycarboxylic acid receptor 1 (HCA1 or HCAR1) and is expressed in the adipose tissue, skeletal muscle, and brain (20,29). GPR81 is highly expressed in most tumors, including those in the pancreas, colon, liver, breast, lung, and cervix) (30, 31).…”

Section: G Protein-coupled Receptor 81 (Gpr81)mentioning

confidence: 99%

Lactic Acid: A Novel Signaling Molecule in Early Pregnancy?

Huang

Muyayalo

et al. 2020

Front. Immunol.

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Aerobic glycolysis is a recognized feature shared by tumors, leading to the accumulation of lactic acid in their local microenvironments. Like the tumors, the blastocysts, placenta, trophoblasts and decidual immune cells can also produce a large amount of lactic acid through aerobic glycolysis during the early pregnancy. Moreover, the placenta expresses the transporters of the lactic acid. While several studies have described the role of lactic acid in the tumor microenvironment, especially lactic acid's modulation of immune cells, the role of lactic acid produced during pregnancy is still unclear. In this paper, we reviewed the scientific evidence detailing the effects of lactic acid in the tumor microenvironment. Based on the influence of the lactic acid on immune cells and tumors, we proposed that lactic acid released in the unique uterine environment could have similar effects on the trophoblast cells and immune cells during the early pregnancy.

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“…Moreover, recent evidence suggests that it acts as an antidepressant in an animal model of depression [17]. Since central cyclic AMP (cAMP) signalling was found to be reduced in depressed patients, this could potentially be explained by the ability of LL to increase cAMP responses in astrocytes and some neuronal phenotypes [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

et al. 2018

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The importance of astrocytic l-lactate (LL) for normal functioning of neural circuits such as those regulating learning/memory, sleep/wake state, autonomic homeostasis, or emotional behaviour is being increasingly recognised. l-Lactate can act on neurones as a metabolic or redox substrate, but transmembrane receptor targets are also emerging. A comparative review of the hydroxy-carboxylic acid receptor (HCA1, formerly known as GPR81), Olfactory Receptor Family 51 Subfamily E Member 2 (OR51E2), and orphan receptor GPR4 highlights differences in their LL sensitivity, pharmacology, intracellular coupling, and localisation in the brain. In addition, a putative Gs-coupled receptor on noradrenergic neurones, LLRx, which we previously postulated, remains to be identified. Next-generation sequencing revealed several orphan receptors expressed in locus coeruleus neurones. Screening of a selection of these suggests additional LL-sensitive receptors: GPR180 which inhibits and GPR137 which activates intracellular cyclic AMP signalling in response to LL in a heterologous expression system. To further characterise binding of LL at LLRx, we carried out a structure–activity relationship study which demonstrates that carboxyl and 2-hydroxyl moieties of LL are essential for triggering d-lactate-sensitive noradrenaline release in locus coeruleus, and that the size of the LL binding pocket is limited towards the methyl group position. The evidence accumulating to date suggests that LL acts via multiple receptor targets to modulate distinct brain functions.

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Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

Cited by 64 publications

References 67 publications

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Lactic Acid: A Novel Signaling Molecule in Early Pregnancy?

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

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