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

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

doi:10.1002/mds.29525

Article (Périodiques scientifiques)

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

Grossmann, Dajana; Malburg, Nina; Glaß, Hannes et al.

2023 • In Movement disorders : official journal of the Movement Disorder Society

Peer reviewed

Permalien
https://hdl.handle.net/10993/55633

DOI
10.1002/mds.29525

PubMed
37449534

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[en] Background: 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). Objective: 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.<h4>Methods</h4>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. Results: 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. Conclusions: 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.

Disciplines :

Biochimie, biophysique & biologie moléculaire

Auteur, co-auteur :

Grossmann, Dajana

Malburg, Nina

Glaß, Hannes

Weeren, Veronika

Sondermann, Verena

Pfeiffer, Julia F.

Petters, Janine

Lukas, Jan

Seibler, Philip

Klein, Christine

GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology

Hermann, Andreas

Co-auteurs externes :

yes

Langue du document :

Anglais

Titre :

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

Date de publication/diffusion :

2023

Titre du périodique :

Movement disorders : official journal of the Movement Disorder Society

ISSN :

0885-3185

Peer reviewed :

Peer reviewed

URL complémentaire :

https://doi.org/10.1002/mds.29525

Projet FnR :

FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald

Disponible sur ORBilu :

depuis le 18 juillet 2023

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