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Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.

Vazquez A - PLoS ONE (2013)

Bottom Line: In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system.The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates.Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Center for Systems Biology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, United States of America. vazqueal@umdnj.edu

ABSTRACT
The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM) corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM) is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

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Metabolic flux distribution in Phase 2.Rate of selected reactions that are relevant to the metabolic state of Phase 2. The lines represent the median over simulated sets of kinetics parameters and the error bars are the 90% confidence intervals. The white, grey and yellow backgrounds represent Phase 1, 2 and 3, respectively. Abbreviations: PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PEPCK, phosphoglycerate carboxykinase; C1TS, C1-tetrahydrofolate synthase, a tri-functional enzyme that processes three distinct enzymatic activities, 5,10-methylenetetrahydrofolate (mlthf) dehydrogenase, 5,10-methenyltetrahydrofolate (methf) cyclohydrolase and 10-formyltetrahydrofolate (10fthf) synthetase.
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pone-0063822-g002: Metabolic flux distribution in Phase 2.Rate of selected reactions that are relevant to the metabolic state of Phase 2. The lines represent the median over simulated sets of kinetics parameters and the error bars are the 90% confidence intervals. The white, grey and yellow backgrounds represent Phase 1, 2 and 3, respectively. Abbreviations: PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PEPCK, phosphoglycerate carboxykinase; C1TS, C1-tetrahydrofolate synthase, a tri-functional enzyme that processes three distinct enzymatic activities, 5,10-methylenetetrahydrofolate (mlthf) dehydrogenase, 5,10-methenyltetrahydrofolate (methf) cyclohydrolase and 10-formyltetrahydrofolate (10fthf) synthetase.

Mentions: In this phase there is a mixed utilization of lactate and glucose as energy substrates (Figure 1a and 1b). There are also significant changes in the way lactate is metabolized (Figure 2). As in Phase 1, lactate is converted to pyruvate. Part of the pyruvate is used for oxidative phosphorylation in the mitochondria, with a magnitude that gradually decreases with increasing the concentration of protein aggregates (Figure 2, brown). This behavior is quantified by the gradual decrease of the ATP synthase rate (Figure 2, ATP synthase panel), which matches the predicted decrease in mitochondrial density (Figure 1e). The remaining part of pyruvate is converted to 3-phosphoglycerate in a glyconeogenesis like fashion (Figure 2, blue). Glucose also contributes to the production of 3-phosphoglycerate via the first steps of glycolysis. 3-phosphoglycerate is then metabolized through an alternative pathway for energy generation involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system (SOG pathway, Figure 2, green), first reported in [26]. This pathway generates 4 molecules of ATP per molecule of glucose and 2 molecules of ATP per molecule of lactate. In this phase both the partial oxidative phosphorylation of lactate and the SOG pathway sustain the basal energy demand. The upregulation of the SOG pathway is accompanied by a change from ammonia to histidine as the nitrogen source (Figure 2, histidine uptake panel) and a switch from ammonia uptake to ammonia excretion (Figure 2, ammonia excretion panel).


Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.

Vazquez A - PLoS ONE (2013)

Metabolic flux distribution in Phase 2.Rate of selected reactions that are relevant to the metabolic state of Phase 2. The lines represent the median over simulated sets of kinetics parameters and the error bars are the 90% confidence intervals. The white, grey and yellow backgrounds represent Phase 1, 2 and 3, respectively. Abbreviations: PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PEPCK, phosphoglycerate carboxykinase; C1TS, C1-tetrahydrofolate synthase, a tri-functional enzyme that processes three distinct enzymatic activities, 5,10-methylenetetrahydrofolate (mlthf) dehydrogenase, 5,10-methenyltetrahydrofolate (methf) cyclohydrolase and 10-formyltetrahydrofolate (10fthf) synthetase.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646825&req=5

pone-0063822-g002: Metabolic flux distribution in Phase 2.Rate of selected reactions that are relevant to the metabolic state of Phase 2. The lines represent the median over simulated sets of kinetics parameters and the error bars are the 90% confidence intervals. The white, grey and yellow backgrounds represent Phase 1, 2 and 3, respectively. Abbreviations: PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PEPCK, phosphoglycerate carboxykinase; C1TS, C1-tetrahydrofolate synthase, a tri-functional enzyme that processes three distinct enzymatic activities, 5,10-methylenetetrahydrofolate (mlthf) dehydrogenase, 5,10-methenyltetrahydrofolate (methf) cyclohydrolase and 10-formyltetrahydrofolate (10fthf) synthetase.
Mentions: In this phase there is a mixed utilization of lactate and glucose as energy substrates (Figure 1a and 1b). There are also significant changes in the way lactate is metabolized (Figure 2). As in Phase 1, lactate is converted to pyruvate. Part of the pyruvate is used for oxidative phosphorylation in the mitochondria, with a magnitude that gradually decreases with increasing the concentration of protein aggregates (Figure 2, brown). This behavior is quantified by the gradual decrease of the ATP synthase rate (Figure 2, ATP synthase panel), which matches the predicted decrease in mitochondrial density (Figure 1e). The remaining part of pyruvate is converted to 3-phosphoglycerate in a glyconeogenesis like fashion (Figure 2, blue). Glucose also contributes to the production of 3-phosphoglycerate via the first steps of glycolysis. 3-phosphoglycerate is then metabolized through an alternative pathway for energy generation involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system (SOG pathway, Figure 2, green), first reported in [26]. This pathway generates 4 molecules of ATP per molecule of glucose and 2 molecules of ATP per molecule of lactate. In this phase both the partial oxidative phosphorylation of lactate and the SOG pathway sustain the basal energy demand. The upregulation of the SOG pathway is accompanied by a change from ammonia to histidine as the nitrogen source (Figure 2, histidine uptake panel) and a switch from ammonia uptake to ammonia excretion (Figure 2, ammonia excretion panel).

Bottom Line: In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system.The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates.Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Center for Systems Biology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, United States of America. vazqueal@umdnj.edu

ABSTRACT
The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM) corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM) is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

Show MeSH
Related in: MedlinePlus