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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 phases with increasing the concentration of protein aggregates.a)–d) Exchange flux as a function of the protein aggregates concentration. e) and f) Relative volume fraction occupied by mitochondria e) and cytosolic enzymes f). 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 background represent phase 1, 2 and 3, respectively.
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pone-0063822-g001: Metabolic phases with increasing the concentration of protein aggregates.a)–d) Exchange flux as a function of the protein aggregates concentration. e) and f) Relative volume fraction occupied by mitochondria e) and cytosolic enzymes f). 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 background represent phase 1, 2 and 3, respectively.

Mentions: We observe significant changes in the model predicted exchange fluxes when increasing the concentration of protein aggregates (Figure 1). Specifically, we can clearly distinguish three major phases depending on whether lactate or glucose is used as the energy substrate and whether ammonia or histidine is used as the nitrogen source. Below protein aggregate concentrations of 6 mM, lactate is the preferred energy substrate and ammonia the preferred nitrogen source (Phase 1, white background). From 6 to 8.6 mM there is a transition to a mixed use of lactate and glucose as energy substrates and a gradual change from ammonia to histidine as nitrogen source, with concomitant excretion of ammonia (Phase 2, grey background). From 8.6 to 9.3 mM there is a complete switch to glucose as the energy substrate and histidine as the nitrogen substrate, with concomitant excretion of lactate and ammonia (Phase 3, yellow background). Finally, beyond 9.3 mM the protein aggregates occupy almost all the 40% of the intracellular volume accessible to macromolecules and there is no room for the allocation of metabolic enzymes, ribosomes or mitochondria (unfeasible region). In this latter regime the cell is predicted to be incapable of generating the basal energy required for cell maintenance and therefore should die.


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

Vazquez A - PLoS ONE (2013)

Metabolic phases with increasing the concentration of protein aggregates.a)–d) Exchange flux as a function of the protein aggregates concentration. e) and f) Relative volume fraction occupied by mitochondria e) and cytosolic enzymes f). 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 background represent phase 1, 2 and 3, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646825&req=5

pone-0063822-g001: Metabolic phases with increasing the concentration of protein aggregates.a)–d) Exchange flux as a function of the protein aggregates concentration. e) and f) Relative volume fraction occupied by mitochondria e) and cytosolic enzymes f). 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 background represent phase 1, 2 and 3, respectively.
Mentions: We observe significant changes in the model predicted exchange fluxes when increasing the concentration of protein aggregates (Figure 1). Specifically, we can clearly distinguish three major phases depending on whether lactate or glucose is used as the energy substrate and whether ammonia or histidine is used as the nitrogen source. Below protein aggregate concentrations of 6 mM, lactate is the preferred energy substrate and ammonia the preferred nitrogen source (Phase 1, white background). From 6 to 8.6 mM there is a transition to a mixed use of lactate and glucose as energy substrates and a gradual change from ammonia to histidine as nitrogen source, with concomitant excretion of ammonia (Phase 2, grey background). From 8.6 to 9.3 mM there is a complete switch to glucose as the energy substrate and histidine as the nitrogen substrate, with concomitant excretion of lactate and ammonia (Phase 3, yellow background). Finally, beyond 9.3 mM the protein aggregates occupy almost all the 40% of the intracellular volume accessible to macromolecules and there is no room for the allocation of metabolic enzymes, ribosomes or mitochondria (unfeasible region). In this latter regime the cell is predicted to be incapable of generating the basal energy required for cell maintenance and therefore should die.

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