Objective: This study examines the pathogenic effect of the LRRK2 I1371V mutation on mitochondrial dysfunction, as a result of ER calcium dysregulation, and impaired mitophagy owing to a faulty degradation system in iPSC derived astrocytes. This study examines the pathogenic effect of the LRRK2 I1371V mutation on mitochondrial dysfunction, as a result of ER calcium dysregulation, and impaired mitophagy owing to a faulty degradation system in iPSC derived astrocytes.

Background: Mitochondria constantly communicate with the endoplasmic reticulum (ER) and lysosomes, forming a dynamic network crucial for cellular homeostasis. These interactions help regulate calcium levels and energy production. In PD, astrocytes play a key role in supporting neurons, but their function is disrupted because of the LRRK2 I1371V mutation. One of the biggest impairments is seen in the impairment of ATP production, pointing directly to mitochondrial dysfunction. Understanding how mitochondrial deficits arise in the context of impaired astrocytic function will provide insights into the pathophysiology of LRRK2-linked PD.

Method: We investigated how the LRRK2 I1371V mutation affects ER calcium homeostasis, mitochondrial function, and mitophagy. Calcium dynamics were measured using live-cell imaging, mitochondrial function was assessed through ATP production and membrane potential assays, and mitophagy was evaluated using immunostaining and lysosomal degradation assays.

Results: Astrocytes carrying the LRRK2 I1371V mutation showed clear signs of mitochondrial stress, with depolarization and an increase in mitochondrial ROS. This was attributed to ER stress, initiated by excess influx of calcium via the SOCE pathway, which interfered with protein synthesis and led to calcium overload in mitochondria through MAMs. Under normal circumstances, stressed mitochondria would trigger mitophagy to eliminate the damaged structures, but in these cells, defective lysosomal and proteasomal pathways could not effectively eliminate them. These findings highlight the role of the LRRK2 I1371V mutation in worsening mitochondrial dysfunction through multiple pathways.

Conclusion: These findings highlight how the LRRK2 I1371V mutation drives mitochondrial dysfunction by disrupting calcium balance, triggering ER stress, and impairing the cell’s ability to clear damaged mitochondria.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-i1371v-mutation-induces-er-stress-mitochondrial-dysfunction-and-impaired-mitophagy-in-parkinsons-disease-astrocytes/