title: Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.
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.
authors.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
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
mesh_terms: D000641:Ammonia / Q000378:metabolism; D002477:Cells / Q000378:metabolism; D003198:Computer Simulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D064688:Metabolic Flux Analysis; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D020836:Protein Structure, Quaternary
chemical_list: D019344:Lactic Acid; D000641:Ammonia; D005947:Glucose