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Methylglyoxal, the dark side of glycolysis.

Allaman I, Bélanger M, Magistretti PJ - Front Neurosci (2015)

Bottom Line: There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons.While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered.Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland.

ABSTRACT
Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the proposed mechanism by which higher glycolytic rates in astrocytes may provide a mechanism limiting MG toxicity in neurons. Glycolysis in both astrocytes and neurons leads to the production of the toxic MG by-product. MG is detoxified by both cell types through the glyoxalase system (GLO), producing D-lactate (D-lac). In normal and stimulated conditions (ANLS) glucose utilization and its processing through the glycolysis is tilted toward astrocytes, which release L-lactate (lactate) that can be used by neurons as a mitochondrial energy substrate. Due to the high activity of the MG-detoxifying glyoxalase system in astrocytes, these cells are well equipped to handle MG accumulation and toxicity. Because they display lower glyoxalase system activity, neurons benefit from the glycolytic processing of glucose in astrocytes since they are spared from: (1) MG accumulation and toxicity (2) alterations in their antioxidant status (through the mobilization of GSH by Glo-1), and (3) the burden of mounting an enzymatic system to process MG. See text for more details. Green arrows highlight the prevalent routes of glucose utilization in brain cells.
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Figure 3: Schematic representation of the proposed mechanism by which higher glycolytic rates in astrocytes may provide a mechanism limiting MG toxicity in neurons. Glycolysis in both astrocytes and neurons leads to the production of the toxic MG by-product. MG is detoxified by both cell types through the glyoxalase system (GLO), producing D-lactate (D-lac). In normal and stimulated conditions (ANLS) glucose utilization and its processing through the glycolysis is tilted toward astrocytes, which release L-lactate (lactate) that can be used by neurons as a mitochondrial energy substrate. Due to the high activity of the MG-detoxifying glyoxalase system in astrocytes, these cells are well equipped to handle MG accumulation and toxicity. Because they display lower glyoxalase system activity, neurons benefit from the glycolytic processing of glucose in astrocytes since they are spared from: (1) MG accumulation and toxicity (2) alterations in their antioxidant status (through the mobilization of GSH by Glo-1), and (3) the burden of mounting an enzymatic system to process MG. See text for more details. Green arrows highlight the prevalent routes of glucose utilization in brain cells.

Mentions: According to this hypothesis, neurons meet their high energetic requirements by utilizing astrocyte-derived lactate (produced from extracellular glucose or glycogen pools), which can be oxidized in the TCA cycle following its conversion to pyruvate. Such a scenario allows neurons to generate energy on demand without compromising their antioxidant status (through the mobilization of GSH by Glo-1), and leaves astrocytes with most of the MG burden (Figure 3). In line with this, the observation that astrocytes protect neurons against MG toxicity in a co-culture model (Bélanger et al., 2011b), suggests another level of astrocyte-neuron cooperativity. For instance, a highly efficient glyoxalase system in astrocytes may reinforce neuronal protection against MG potentially leaking from the periphery, the cerebrospinal fluid or surrounding cells. As a whole, such view support the concept of an “outsourced glycolysis” to astrocytes in the brain as suggested by Barros (2013).


Methylglyoxal, the dark side of glycolysis.

Allaman I, Bélanger M, Magistretti PJ - Front Neurosci (2015)

Schematic representation of the proposed mechanism by which higher glycolytic rates in astrocytes may provide a mechanism limiting MG toxicity in neurons. Glycolysis in both astrocytes and neurons leads to the production of the toxic MG by-product. MG is detoxified by both cell types through the glyoxalase system (GLO), producing D-lactate (D-lac). In normal and stimulated conditions (ANLS) glucose utilization and its processing through the glycolysis is tilted toward astrocytes, which release L-lactate (lactate) that can be used by neurons as a mitochondrial energy substrate. Due to the high activity of the MG-detoxifying glyoxalase system in astrocytes, these cells are well equipped to handle MG accumulation and toxicity. Because they display lower glyoxalase system activity, neurons benefit from the glycolytic processing of glucose in astrocytes since they are spared from: (1) MG accumulation and toxicity (2) alterations in their antioxidant status (through the mobilization of GSH by Glo-1), and (3) the burden of mounting an enzymatic system to process MG. See text for more details. Green arrows highlight the prevalent routes of glucose utilization in brain cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321437&req=5

Figure 3: Schematic representation of the proposed mechanism by which higher glycolytic rates in astrocytes may provide a mechanism limiting MG toxicity in neurons. Glycolysis in both astrocytes and neurons leads to the production of the toxic MG by-product. MG is detoxified by both cell types through the glyoxalase system (GLO), producing D-lactate (D-lac). In normal and stimulated conditions (ANLS) glucose utilization and its processing through the glycolysis is tilted toward astrocytes, which release L-lactate (lactate) that can be used by neurons as a mitochondrial energy substrate. Due to the high activity of the MG-detoxifying glyoxalase system in astrocytes, these cells are well equipped to handle MG accumulation and toxicity. Because they display lower glyoxalase system activity, neurons benefit from the glycolytic processing of glucose in astrocytes since they are spared from: (1) MG accumulation and toxicity (2) alterations in their antioxidant status (through the mobilization of GSH by Glo-1), and (3) the burden of mounting an enzymatic system to process MG. See text for more details. Green arrows highlight the prevalent routes of glucose utilization in brain cells.
Mentions: According to this hypothesis, neurons meet their high energetic requirements by utilizing astrocyte-derived lactate (produced from extracellular glucose or glycogen pools), which can be oxidized in the TCA cycle following its conversion to pyruvate. Such a scenario allows neurons to generate energy on demand without compromising their antioxidant status (through the mobilization of GSH by Glo-1), and leaves astrocytes with most of the MG burden (Figure 3). In line with this, the observation that astrocytes protect neurons against MG toxicity in a co-culture model (Bélanger et al., 2011b), suggests another level of astrocyte-neuron cooperativity. For instance, a highly efficient glyoxalase system in astrocytes may reinforce neuronal protection against MG potentially leaking from the periphery, the cerebrospinal fluid or surrounding cells. As a whole, such view support the concept of an “outsourced glycolysis” to astrocytes in the brain as suggested by Barros (2013).

Bottom Line: There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons.While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered.Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland.

ABSTRACT
Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.

No MeSH data available.


Related in: MedlinePlus