Α-SYNUCLEIN OLIGOMERS INDUCE MITOCHONDRIAL DYSFUNCTION AND TRIGGER EXTRACELLULAR MITOCHONDRIAL RELEASE: IMPLICATIONS FOR ASTROCYTE-NEURON CROSSTALK

Astrocytes play a crucial role in neuroprotection, especially in aging and neurodegenerative disorders like Parkinson's Disease (PD). PD is characterized by α-synuclein aggregation, mitochondrial dysfunction, and increased reactive oxygen species (ROS), contributing to neuronal death. Recent studies suggest that astrocytes may transfer mitochondria to neurons, offering neuroprotective effects.This study investigated the impact of α-synuclein oligomers (α-SO) on astrocytes' neuroprotective properties, specifically focusing on their mitochondrial donation capacity to neurons. Murine astrocytes were treated with α-SO for 24h. Mitochondrial gene expression, morphology, and dynamics were evaluated using RT-PCR and immunocytochemistry. Oxygraphy assessed mitochondrial respiratory properties. Flow cytometry quantified and evaluated functional properties of released extracellular mitochondria. Data revealed that α-SO increased mitochondrial biogenesis, evidenced by upregulated PGC-1α expression, and reduced DRP1-mediated mitochondrial fission. Treatment resulted in decreased mitochondrial membrane potential (MMP) and increased ROS levels. Respirometry analysis showed higher basal respiration and proton leak. Cytometry revealed increased mitochondrial release, which exhibited elevated MMP, indicating functional state. Human astrocytes showed similar profiles. Investigation of transfer pathways demonstrated CD38 upregulation. Neurons treated with conditioned medium from α-SO-exposed astrocytes showed enhanced mitochondrial uptake. Surprisingly, α-SO increased astrocytic mitochondrial release to neurons, suggesting a neuroprotective role of astrocytes in synucleinopathy pathogenesis. This finding highlights the significance of astrocytic mitochondrial transfer in neuroprotection and its potential therapeutic implications for understanding and treating synucleinopathies.
Ethics Committee approval: A23/21-006-18.