Reference : Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	To cite this reference:	http://hdl.handle.net/10993/55633

Title :	Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons
Language :	English
Author, co-author :	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 [> >]
Publication date :	2023
Journal title :	Movement disorders : official journal of the Movement Disorder Society
Peer reviewed :	Yes
ISSN :	0885-3185
Abstract :	[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.
Target :	Researchers ; Students
Permalink :	http://hdl.handle.net/10993/55633
DOI :	10.1002/mds.29525
Other URL :	https://doi.org/10.1002/mds.29525
FnR project :	FnR ; FNR9631103 > Anne Grünewald > Model IPD > Modelling Idiopathic Parkinson’S Disease-associated Somatic Variation In Dopaminergic Neurons > 01/01/2016 > 31/12/2022 > 2015

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