Lactate sensitive transcription factor network in L6 cells: activation of
            <i>MCT1</i>
            and mitochondrial biogenesis

Hashimoto, Takeshi; Hussien, Rajaa; Oommen, Saji; Gohil, Kishorchandra; Brooks, George A.

doi:10.1096/fj.07-8174com

Cited by 370 publications

(416 citation statements)

References 54 publications

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“…Previous observations reported the ability of L-lactate to stimulate gene expression in different cell types in culture such as L6 cells, vasculogenic stem cells, mesenchymal stem cells, or fibroblasts although the activation of specific transcription factors (14)(15)(16)(17). In the present study we show that L-lactate induces the expression of key plasticity-related genes, namely, Arc, Zif268, c-Fos, and BDNF in neuronal cultures.…”

Section: Discussionsupporting

confidence: 71%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

402

373

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L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.brain energy metabolism | learning and memory | astrocyte-neuron interaction | astrocyte-neuron lactate shuttle T he transfer of L-lactate from astrocytes to neurons was recently shown to be necessary for the establishment of longterm memory (LTM) in an inhibitory avoidance (IA) paradigm and for the maintenance of in vivo long-term potentiation (LTP) in the rodent hippocampus (1). This key role of L-lactate in neuronal plasticity mechanisms was demonstrated in experiments in which specific pharmacological and gene expression down-regulation interventions were implemented to prevent the production of L-lactate from glycogen-which is exclusively localized in astrocytes-and its release from these cells in the hippocampus during behavioral training (1). Such interventions completely prevented the establishment of LTM and their effect was fully reversed by the intrahippocampal administration of L-lactate during the training session. The fact that glucose at equicaloric concentrations only marginally mimicked the rescuing effect of L-lactate was taken as an unexpected indication that the primary mechanism of action of L-lactate on plasticity mechanisms was independent of its ability to act as an energy substrate. A role of L-lactate in memory processes was also recently shown in other behavioral paradigms (2, 3). We therefore set out to investigate the molecular mechanisms at the basis of the function of L-lactate on neuronal plasticity.Molecular mechanisms underlying both LTM and long-term plasticity include the induction of expression of a group of immediate early genes (IEGs) such as early growth response 1 (Zif268 or Egr1), CCAAT/enhancer binding protein (C/EBP), and proto-oncogene c-Fos (c-Fos) as well as activity-regulated cytoskeletal-associated protein (Arc or Arg3.1) as a direct effector protein at the synapse, which all participate to different physiological processes associated with neuronal p...

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Section: Discussionsupporting

confidence: 71%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

402

373

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“…We did not measure the MCT4 lactate transporter because MCT4 plays a role in releasing lactate from muscle to other tissues, not uptake into muscle, and has a much higher Km value for lactate compared with MCT1 (32). Hashimoto et al reported that lactate can be a signal to increase MCT1 and mitochondrial protein expression, but not MCT4 (33). In our study, post-exercise lactate administration increased the blood lactate concentration to approximately 5 mmol/L for 2 h. We speculate that the higher lactate concentration is the result of the increased MCT1 protein expression.…”

Section: Discussionsupporting

confidence: 49%

Chronic Post-Exercise Lactate Administration with Endurance Training Increases Glycogen Concentration and Monocarboxylate Transporter 1 Protein in Mouse White Muscle

Hoshino

Hanawa

Takahashi

et al. 2014

J Nutr Sci Vitaminol

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“…In addition, lactate also functions as a reporter. It controls the expression of mitochondrial factors and activates master genes of metabolic regulation, including nuclear respiratory factor-2 and the peroxisome proliferator activated-receptor g coactivator-1a [63].…”

Section: Reviewmentioning

confidence: 99%

Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.Evolution of the metabolic network and its structure Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid-or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent and counteract perturbations in the flux, many biological control and sensor systems have evolved around the metabolic network. Metabolic pathways provide the cell with energy and supply macromolecular synthesis pathways with their required intermediates. They also balance metabolic systems under a variety of physiological conditions, and act as transducers and sensor systems for environmental conditions and stimuli. In addition, metabolic pathways are essential for crosstalk between metabolic regulatory components and the cellular transcriptome and proteome.As early as the 1960s, the principle that cells alter their gene expression in response to metabolic requirements has been known. The seminal work of Jacob and Monod, investigating the lac operon, uncovered one of the first examples of chemical-genetic regulation, by which bacterial cells adjust their enzyme production to the nutrient supply [3]. However, only recently have the broader implications of this principle emerged. Indeed, changes in the metabolic network not only control the metabolome, but they also have wide-ranging regulatory functions throughout biology.Most of the biochemical mechanisms that link the metabolic network to the transcriptome and proteome are incompletely understood. However, one type of regulation appears to be common: representative network intermediates bind to and modulate sensor function and activity of transcription factors, translational regulators, chromatin, enzymes, RNA molecules, and ion channels. Significant transcriptional changes around these intermediates identified them as reporter metabolites [4,5]. The use of intermediates as activity reporters ne...

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Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis

Cited by 370 publications

References 54 publications

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Chronic Post-Exercise Lactate Administration with Endurance Training Increases Glycogen Concentration and Monocarboxylate Transporter 1 Protein in Mouse White Muscle

Regulatory crosstalk of the metabolic network

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