Journal Article

DZNE-2023-01040

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.

Grossmann, D. ; Malburg, N. ; Glaß, H. ; Weeren, V. ; Sondermann, V. ; Pfeiffer, J. F. ; Petters, J. ; Lukas, J. ; Seibler, P. ; Klein, C. ; Grünewald, A. ; Hermann, A. (Last author)DZNE*

2023
Wiley New York, NY

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Please use a persistent id in citations: doi:10.1002/mds.29525

Abstract: 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.

Keyword(s): Humans (MeSH) ; Parkinson Disease: pathology (MeSH) ; Calcium: metabolism (MeSH) ; Thapsigargin: metabolism (MeSH) ; Mitochondria: pathology (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Protein Kinases: genetics (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Endoplasmic Reticulum: metabolism (MeSH) ; Homeostasis (MeSH) ; PTEN-induced putative kinase ; PINK1 ; Parkin ; Parkinson's disease ; calcium ; mitochondria-ER contact sites ; Calcium ; Thapsigargin ; Protein Kinases ; Ubiquitin-Protein Ligases ; parkin protein

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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