TY  - JOUR
AU  - Grossmann, Dajana
AU  - Malburg, Nina
AU  - Glaß, Hannes
AU  - Weeren, Veronika
AU  - Sondermann, Verena
AU  - Pfeiffer, Julia F
AU  - Petters, Janine
AU  - Lukas, Jan
AU  - Seibler, Philip
AU  - Klein, Christine
AU  - Grünewald, Anne
AU  - Hermann, Andreas
TI  - Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
JO  - Movement disorders
VL  - 38
IS  - 10
SN  - 0885-3185
CY  - New York, NY
PB  - Wiley
M1  - DZNE-2023-01040
SP  - 1822 - 1836
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Parkinson Disease: pathology
KW  - Calcium: metabolism
KW  - Thapsigargin: metabolism
KW  - Mitochondria: pathology
KW  - Dopaminergic Neurons: metabolism
KW  - Protein Kinases: genetics
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Endoplasmic Reticulum: metabolism
KW  - Homeostasis
KW  - PTEN-induced putative kinase (NLM Chemicals)
KW  - PINK1 (Other)
KW  - Parkin (Other)
KW  - Parkinson's disease (Other)
KW  - calcium (Other)
KW  - mitochondria-ER contact sites (Other)
KW  - Calcium (NLM Chemicals)
KW  - Thapsigargin (NLM Chemicals)
KW  - Protein Kinases (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37449534
DO  - DOI:10.1002/mds.29525
UR  - https://pub.dzne.de/record/265796
ER  -