Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons

Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons

It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the...

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Published in:Movement disorders Vol. 38; no. 10; pp. 1822 - 1836
Main Authors: Grossmann, Dajana, Malburg, Nina, Glaß, Hannes, Weeren, Veronika, Sondermann, Verena, Pfeiffer, Julia F, Petters, Janine, Lukas, Jan, Seibler, Philip, Klein, Christine, Grünewald, Anne, Hermann, Andreas
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01-10-2023
Subjects:
Calcium (mitochondrial)
Calcium homeostasis
Calcium influx
Calcium signalling
Dopamine receptors
Endoplasmic reticulum
Homeostasis
Mitochondria
Movement disorders
Neurodegenerative diseases
Neurons
Parkin protein
Parkinson's disease
Pluripotency
PTEN-induced putative kinase
Quality control
Thapsigargin
PINK1
calcium
Parkinson´s disease
mitochondria-ER contact sites
Parkin
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Summary:It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the regulation of mitochondria-endoplasmic reticulum contact sites (MERCSs). The aim of our study was to perform an in-depth analysis of the role of MERCSs and impaired calcium homeostasis in PINK1/Parkin-linked PD. In our study, we used induced pluripotent stem cell-derived dopaminergic neurons from patients with PD with loss-of-function mutations in PINK1 or PRKN. We employed a split-GFP-based contact site sensor in combination with the calcium-sensitive dye Rhod-2 AM and applied Airyscan live-cell super-resolution microscopy to determine how MERCSs are involved in the regulation of mitochondrial calcium homeostasis. Our results showed that thapsigargin-induced calcium stress leads to an increase of the abundance of narrow MERCSs in wild-type neurons. Intriguingly, calcium levels at the MERCSs remained stable, whereas the increased net calcium influx resulted in elevated mitochondrial calcium levels. However, PINK1-PD or PRKN-PD neurons showed an increased abundance of MERCSs at baseline, accompanied by an inability to further increase MERCSs upon thapsigargin-induced calcium stress. Consequently, calcium distribution at MERCSs and within mitochondria was disrupted. Our results demonstrated how the endoplasmic reticulum and mitochondria work together to cope with calcium stress in wild-type neurons. In addition, our results suggests that PRKN deficiency affects the dynamics and composition of MERCSs differently from PINK1 deficiency, resulting in differentially affected calcium homeostasis. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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ISSN:0885-3185
1531-8257
DOI:10.1002/mds.29525