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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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Phase diagram.Predicted metabolic phases as a function of the concentration of protein aggregates and the energy demand. The symbols represent energy demands where, for 50% of the kinetic parameters choices, the glucose uptake starts increasing from zero (circles), the lactate exchange switch from uptake to excretion (squares) and the maximum attainable ATP demand (diamons), as a function of the concentration of protein aggregates. The dashed, solid and dotted lines represent the energy demands where in 5%, 50% and 95% of the kinetic parameter choices the event specified by the corresponding symbol was satisfied, after linear fits to the simulation points.
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pone-0063822-g004: Phase diagram.Predicted metabolic phases as a function of the concentration of protein aggregates and the energy demand. The symbols represent energy demands where, for 50% of the kinetic parameters choices, the glucose uptake starts increasing from zero (circles), the lactate exchange switch from uptake to excretion (squares) and the maximum attainable ATP demand (diamons), as a function of the concentration of protein aggregates. The dashed, solid and dotted lines represent the energy demands where in 5%, 50% and 95% of the kinetic parameter choices the event specified by the corresponding symbol was satisfied, after linear fits to the simulation points.

Mentions: These results can be generalized to situations where the neuronal activity demands more energy than what is required for cell maintenance. More precisely, we can depict the different metabolic phases in the plane of protein aggregate concentration and energy demand (Figure 4). To this end, we determined the energy demand when glucose uptake starts (Phase 1/Phase 2), when lactate uptake switches to lactate excretion (Phase 2/Phase 3) and the maximum energy demand that can be satisfied (Phase 3/Unfeasible region), all as a function of the concentration of protein aggregates.


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

Vazquez A - PLoS ONE (2013)

Phase diagram.Predicted metabolic phases as a function of the concentration of protein aggregates and the energy demand. The symbols represent energy demands where, for 50% of the kinetic parameters choices, the glucose uptake starts increasing from zero (circles), the lactate exchange switch from uptake to excretion (squares) and the maximum attainable ATP demand (diamons), as a function of the concentration of protein aggregates. The dashed, solid and dotted lines represent the energy demands where in 5%, 50% and 95% of the kinetic parameter choices the event specified by the corresponding symbol was satisfied, after linear fits to the simulation points.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0063822-g004: Phase diagram.Predicted metabolic phases as a function of the concentration of protein aggregates and the energy demand. The symbols represent energy demands where, for 50% of the kinetic parameters choices, the glucose uptake starts increasing from zero (circles), the lactate exchange switch from uptake to excretion (squares) and the maximum attainable ATP demand (diamons), as a function of the concentration of protein aggregates. The dashed, solid and dotted lines represent the energy demands where in 5%, 50% and 95% of the kinetic parameter choices the event specified by the corresponding symbol was satisfied, after linear fits to the simulation points.
Mentions: These results can be generalized to situations where the neuronal activity demands more energy than what is required for cell maintenance. More precisely, we can depict the different metabolic phases in the plane of protein aggregate concentration and energy demand (Figure 4). To this end, we determined the energy demand when glucose uptake starts (Phase 1/Phase 2), when lactate uptake switches to lactate excretion (Phase 2/Phase 3) and the maximum energy demand that can be satisfied (Phase 3/Unfeasible region), all as a function of the concentration of protein aggregates.

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