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The monocarboxylate transporter MCT4 : mechanism of regulation in astrocytes and its putative role in cerebral ischemia

Abstract

explains its small fraction of the total body weight (2 %), the brain contributors for 20 % and 25 % respecting the total oxygen and glucose consumption of the whole body. Loose, glucose has been considered to be the energy substrate par excellence for the brain. However, evidence accumulated over the last half century observed an important role for the monocarboxylate lactate in fulfilling the energy needs of neurons. This is particularly true during physical neural activation and in Pathological conditions. Lactate transport into and out of the cell is mediated by a family of proton-linked transporters called for monocarboxylate transporters (MCTS). In the central nervous system, only three of them have been well characterised: MCT2 is the predominant neural isoform, while the other non -governmental cell types of the brain express the ubiquitous isoform MCT1. Quite recently, the MCT4 isoform has been described in astrocytes. Due to its high transport capacity compared to the other two isoforms, MCT4 is particularly adapted for glycolytic cells. Fault of its recent discovery in the brain, nothing was known about its rules in the central nervous system. Here we show that MCT4 is regulated by oxygen levels in primary crops of astrocytes in a time- and concentration-dependent manner via the hypoxia induced factor-la (HIF-la). Moreover, we showed that MCT4 expression is essential for astrocyte survival under low oxygen conditions. In parallel, we investigate the possible involvement of the pyruvate kinase isoform pKM2, a strong improvement of glycolysis, in its regulations. Then we saw that MCT4 expression, as well as the expression of the other two MCT isoforms, is altered in a murine model of stroke. Surprisingly, neurons started to express MCT4, as well as MCT1, under these conditions. Altogether, this data suggests that MCT4, due to its high transport capacity for lactate, may be the isoform that can be expected to operate a major metabolic adaptation in response to Pathological situations that alter metabolic homeostasis of the brain. — The brain accounts for 2 % of total body weight, but contributes 20 % of total oxygen consumption and 25 % of glucose at rest. Glucose is considered to be the energy substrate par excellence for the brain. However, for the last half century now, more and more work has shown that lactate plays a major role in brain metabolism and is able to meet the energy needs of neurons. Lactate is particularly necessary during neural activation as well as in pathological conditions. The transport of lactate through the haemato-encephalic barrier and through the cell membranes is carried out by the monocarboxylate carrier family (MCTS). In the central nervous system, only three were described: MCT2 is considered the neural carrier, whereas the other cell types that make up the brain express the ubiquitous isoform MCT1. Recently, the isoform MCT4 has been reported on astrocytes. Due to its high transport capacity for lactate, MCT4 is particularly suitable to support the metabolism of highly glycolytic cells, such as astrocytes. Due to its very recent discovery, the aspects including its regulation and role in the brain are currently unknown. The results presented in this work first demonstrate that the expression of MCT4 is regulated by oxygen levels in cortical astrocyte cultures through the HIF-la transcription factor. Moreover, we have demonstrated that the expression of MCT4 is essential for astrocyte survival when the oxygen level decreases. At the same time, preliminary findings suggest that isoform 2 of pyruvate kinase, a powerful glycolysis regulator, could play a role in regulating MCT4. In the second part of the work we demonstrated that the expression of MCT4, as well as that of MCT1 and MCT2, is altered in a murine model of cerebral ischaemia. Surprisingly, neurons express MCT4 in this condition, whereas this is not the case in physiological conditions. Taking these results into account, we suggest that MCT4, due to its particularly high transport capacity for lactate, represents the MCT, which allows cells in the central nervous system, in particular astrocytes and neurons, to adapt to very severe disturbances of the metabolic homeostasy of the brain that occur in pathological conditions.

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