Objective: This study explores lipid metabolic alterations in human astrocytes carrying the A53T α-synuclein mutation and examines their link to mitochondrial organization and cellular bioenergetics.

Background: Accumulation of α-synuclein in Parkinson’s disease (PD) both reflects and contributes to widespread metabolic disturbances. While neuronal dysfunction has been widely investigated, the contribution of astrocytes to these metabolic changes remains unclear. Astrocytes are essential for maintaining neuronal energy balance and play an important role in regulating lipid and cholesterol homeostasis. Alterations in these pathways may compromise astrocyte–neuron metabolic coupling and contribute to neurodegenerative processes.

Method: Human iPSC–derived astrocytes carrying the A53T α-synuclein mutation were characterized using an integrated multi-omics approach that combines transcriptomics, proteomics, and metabolomics. Functional imaging assays using Mitotracker and TMRE assessed mitochondrial organization and activity. Lipid metabolism was evaluated through BODIPY-based imaging of lipid droplets and biochemical quantification of intracellular cholesterol levels.

Results: Multi-omics analysis points to metabolism as a key feature of dysregulation in A53T astrocytes. Several metabolic pathways are affected, including those involved in glucose utilization and lactate metabolism, alongside significant alterations in lipid and cholesterol homeostasis. Imaging experiments reveal a clear increase in lipid droplet accumulation in mutant astrocytes, whereas biochemical assays show reduced total cholesterol levels compared with control cells. These lipid-related changes occur together with an increase in mitochondrial mass and rearrangement of mitochondrial networks toward a hyperfused architecture. Despite these changes, mitochondrial respiration and overall bioenergetic capacity remain compromised.

Conclusion: A53T astrocytes show clear disturbances in lipid homeostasis, which overlap with mitochondrial structural remodeling, suggesting a compensatory response to metabolic stress. Despite this adaptation, mitochondrial respiration remains impaired. Considering the lipid-binding nature of α-synuclein, these findings suggest that disrupted lipid handling may contribute to mitochondrial stress in PD astrocytes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disrupted-lipid-homeostasis-and-mitochondrial-remodeling-in-a53t-%ce%b1-synuclein-astrocytes/