Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia‐inducible factor‐1α‐mediated transcriptional regulation

Abstract

The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode.

Effects of hypoxia on proliferation and osteogenic differentiation of periodontal ligament stem cells: an in vitro and in vivo study

“…Low oxygen tension is a potent differentiation inducer of numerous cell types and an effective stimulus of gene expression (Rosafio and Pellerin, 2013). Thus, we evaluated the effects of reduced oxygen tension on HPDLSCs proliferation and the influence on osteogenic capability.…”

Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures

“…MCT4 expression was previously shown to be up-regulated, together with many glycolytic enzymes such as transcription factor hypoxia-inducible factor-1<alpha> (HIF-1<alpha>) [9]. The promoter region of the MCT4 gene contains hypoxiaresponse elements, to which HIF-1<alpha> can bind to activate transcription [27].…”

“…The promoter region of the MCT4 gene contains hypoxiaresponse elements, to which HIF-1<alpha> can bind to activate transcription [27]. We previously demonstrated that neuronalenriched cultures were non-resistant to OGD in the absence of astrocytes, while OGD up-regulated MCT4 expression at the mRNA and protein levels via HIF-1<alpha>-mediated transcriptional regulation [9].…”

“…MCT1-4 are proton symporters that mediate the transmembrane transport of lactate, pyruvate, and ketone bodies [7]; MCT2 is expressed primarily in neurons in the brain, while MCT4 is expressed almost exclusively in astrocytes [8]. During hypoxia/ischemia, lactate released from astrocytes is taken up by neurons and stored for energy via up-regulation of MCT4 expression [9]. Glial fibrillary acidic protein (GFAP) is an astrocyte-differentiation marker and is considered to be an important element in astrocyte differentiation and in the reactive response to central nervous system injury [10].…”

The polymorphic and contradictory aspects of intermittent hypoxia

“…Although the exact cellular sources of such IH-induced detrimental effects are still incompletely defined, it is likely that a portion of such deleterious effects is ascribable to activation of astroglia and subsequent loss of buffering functions that ultimately contribute to pathological processes, such as increased glial proliferation and microglial activation (63,179). Astroglial and microglial cells play critical roles in regional blood flow regulation and inflammatory processes in the brain as well as critical coordination of bioenergetics through lactate transport (22,140,155). Activated microglia express high levels of the inducible isoform of NOS (iNOS) and COX-2, with both enzymes initiating pathways ultimately leading to generation and propagation of ROS.…”