Metabolic States Following Accumulation of Intracellular Aggregates: Implications for Neurodegenerative Diseases

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.细胞内聚集物的形成是多种神经退行性疾病的常见病因。线粒体功能缺陷与氧化应激被认为是细胞内聚集物积累与细胞死亡之间的主要机制性关联。本研究提出「拥挤诱导的代谢性细胞死亡」作为替代假说。本研究利用神经元代谢模型，预测随着蛋白质聚集物浓度升高，神经元会经历三个不同的代谢阶段：第一阶段（0~6 mM）对应正常神经元状态，此时神经元活动通过乳酸的氧化磷酸化得以维持；第二阶段（6~8.6 mM）以乳酸与葡萄糖混合作为能量底物的利用模式为特征，同时神经元会从摄取氨转为释放氨；第三阶段（8.6~9.3 mM）时，神经元的能量需求将通过糖酵解与一条替代产能途径满足，该途径涉及丝氨酸合成、一碳代谢以及甘氨酸裂解系统的相关反应。该模型还预测，随着蛋白质聚集物浓度升高，神经元的最大能量生成能力会逐渐下降。当蛋白质聚集物浓度达到约9.3 mM时，神经元的最大能量生成能力最终降为零，预示神经元活动将停止。