%0 Journal Article
%A Grossmann, Dajana
%A Malburg, Nina
%A Glaß, Hannes
%A Weeren, Veronika
%A Sondermann, Verena
%A Pfeiffer, Julia F
%A Petters, Janine
%A Lukas, Jan
%A Seibler, Philip
%A Klein, Christine
%A Grünewald, Anne
%A Hermann, Andreas
%T Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
%J Movement disorders
%V 38
%N 10
%@ 0885-3185
%C New York, NY
%I Wiley
%M DZNE-2023-01040
%P 1822 - 1836
%D 2023
%X 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.
%K Humans
%K Parkinson Disease: pathology
%K Calcium: metabolism
%K Thapsigargin: metabolism
%K Mitochondria: pathology
%K Dopaminergic Neurons: metabolism
%K Protein Kinases: genetics
%K Ubiquitin-Protein Ligases: genetics
%K Endoplasmic Reticulum: metabolism
%K Homeostasis
%K PTEN-induced putative kinase (NLM Chemicals)
%K PINK1 (Other)
%K Parkin (Other)
%K Parkinson's disease (Other)
%K calcium (Other)
%K mitochondria-ER contact sites (Other)
%K Calcium (NLM Chemicals)
%K Thapsigargin (NLM Chemicals)
%K Protein Kinases (NLM Chemicals)
%K Ubiquitin-Protein Ligases (NLM Chemicals)
%K parkin protein (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37449534
%R 10.1002/mds.29525
%U https://pub.dzne.de/record/265796