Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease

Abstract

Introduction: Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson's disease (PD).

Method: To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Differences in bioenergetic features and metabolite exchanges were analyzed between these models to explore potential mechanisms underlying the selective vulnerability of dopaminergic neurons. Bioenergetic rescue analyses were performed to identify potential therapeutic targets for mitigating observed energy failure and metabolic dysfunction in PD models.

Results: All models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeds mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model. Both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models.

Discussion: The predicted differences in ATP contribution between models highlight the bioenergetic differences between these neuronal components, thereby contributing to the selective vulnerability observed in PD. The observed differences in metabolite exchanges reflect distinct metabolic patterns between these neuronal components. Additionally, mitochondrial ornithine transaminase was predicted to be the potential bioenergetic rescue target for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.

Keywords: Parkinson’s disease; bioenergetics; modeling; non-synaptic; synaptic.

FIGURE 1

The overlapping metabolites, reactions, and genes shared between synaptic and non-synaptic models.

FIGURE 2

Flux comparison of reactions contributing to ATP production in synaptic and non-synaptic models under control and PD conditions. (A) Comparison of ATP contribution reactions in control and PD synaptic models, with the horizontal axis representing ATP contribution reactions and the vertical axis showing the corresponding flux values. (B) Comparison of ATP contribution reactions in control and PD non-synaptic models. In all models, ATP is primarily produced via oxidative phosphorylation (ATPS4mi) and glycolysis, particularly through phosphoglycerate kinase (PGK) and pyruvate kinase (PYK).

FIGURE 3

Flux changes across various subsystems in both synaptic and non-synaptic models, with energy demand (ATPM) ranging from 10 to 100 μmol/gDW/h. (A) Flux changes across different subsystems in the synaptic control model under varying energy demands. (B) Flux changes across different subsystems in the synaptic PD model under varying energy demands. (C) Flux changes across different subsystems in the non-synaptic control model under varying energy demands. (D) Flux changes across different subsystems in the non-synaptic PD model under varying energy demands. The flux from oxidative phosphorylation approaches a plateau at an energy demand of 60 μmol/gDW/h, with only slight increases beyond this threshold, whereas glycolytic flux continues to rise as energy demand increases.

FIGURE 4

ATP contribution proportions across various subsystems with energy demand ranging from 10 to 100 μmol/gDW/h in both synaptic and non-synaptic models. Compared to the non-synaptic model, the synaptic model exhibited a lower energy contribution from oxidative phosphorylation, citric acid cycle, and nucleotide interconversion, but a higher energy contribution primarily from glycolysis.

FIGURE 5

ATP contribution proportions across different subsystems, with energy demand ranging from 10 to 100 μmol/gDW/h, in synaptic control and PD models. In the synaptic PD model, oxidative phosphorylation contributes less to ATP production than in the control model, while glycolysis and the citric acid cycle contribute more.

FIGURE 6

Complex I inhibition in synaptic and non-synaptic models at a minimum ATPM of 10.62 μmol/gDW/h. (A) Comparison of Complex I inhibition between control and PD synaptic models. (B) Comparison of Complex I inhibition between control and PD non-synaptic models. (C) Flux changes of Complex I under varying inhibition in the synaptic models. (D) Flux changes of Complex I under varying inhibition in the non-synaptic models. ATP synthesis via oxidative phosphorylation remained stable up to 70% Complex I inhibition in the synaptic control model and 80% in the synaptic PD model, reflecting higher sensitivity in the PD condition. In the non-synaptic models, ATP synthesis remained stable up to 90% inhibition in the control, with reductions observed at 70% in the PD model.

FIGURE 7

Complex I inhibition in synaptic and non-synaptic models at an ATPM of 20 μmol/gDW/h. (A) Comparison of Complex I inhibition between control and PD synaptic models. (B) Comparison of Complex I inhibition between control and PD non-synaptic models. (C) Flux changes of Complex I under varying inhibition levels in synaptic models. (D) Flux changes of Complex I under varying inhibition levels in non-synaptic models. In the synaptic PD model, an earlier energy inflection point is observed, with lower Complex I flux than in the control model. Changes in ATP synthesis occur at 30% Complex I inhibition in the control model and at 20% in the PD model. In the non-synaptic models, ATP synthesis alterations are evident at 70% inhibition in the control model and 80% in the PD model.