Objective: In the present study we intent to investigate the effect of mutant Miro1 proteins on mitochondrial function and cellular quality control mechanisms in iPSC-derived neurons and the resulting changes on neuronal function and integrity.

Background: Impaired mitochondrial function and dysfunction of clearance pathways are commonly observed in neurodegenerative diseases like Parkinson’s disease (PD). A number of genes causing genetic forms of PD are involved in these pathways, e.g. PARK7, PINK1, PARK2, SNCA or GBA. A candidate gene in this context is RHOT1, coding for the Miro1 protein, which is critically involved in the regulation of mitochondrial function and quality control. In our previous study, we identified first PD patients carrying coding variants in the RHOT1 gene.

Method: We reprogrammed patient-derived fibroblasts into iPSC, which were differentiated into midbrain dopaminergic neurons. IPSC-derived neurons were used to study mitochondrial function by analysis of mitochondrial respiration, ATP synthesis rate, activity of the respiratory chain and mitochondrial quality control.

Results: Previous results from patient-derived fibroblasts carrying PD-associated Miro1 variants revealed alterations of ER-mitochondria contact sites, which leads to impaired calcium homeostasis and changes of cellular quality control. First results from iPSC-derived neurons with mutations in Miro1 show similar phenotypes, including a higher sensitivity against calcium-stress, resulting in increased mitochondrial fragmentation and elevated cytosolic calcium levels. Furthermore, using live cell imaging of Mitotracker and Lysotracker staining in order to analyze the colocalization of mitochondria and lysosomes, we observed alterations of lysosomal clearance pathways.

Conclusion: PD-associated variants of RHOT1/Miro1 cause changes of ER-mitochondrial contact sites, leading to impaired calcium homeostasis and quality control mechanisms in iPSC-derived neurons.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-parkinsons-disease-associated-rhot1-miro1-variants-in-mitochondrial-dysfunction-and-impaired-cellular-quality-control/