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

Autor: Grossmann D; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Malburg N; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Glaß H; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Weeren V; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Sondermann V; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Pfeiffer JF; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Petters J; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany., Lukas J; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.; Center for Transdisciplinary Neurosciences Rostock, University Medical Center Rostock, University of Rostock, Rostock, Germany., Seibler P; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Klein C; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Grünewald A; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Hermann A; Translational Neurodegeneration Section 'Albrecht Kossel,' Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.; Center for Transdisciplinary Neurosciences Rostock, University Medical Center Rostock, University of Rostock, Rostock, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen Rostock/Greifswald, Rostock, Germany.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2023 Oct; Vol. 38 (10), pp. 1822-1836. Date of Electronic Publication: 2023 Jul 14.
DOI: 10.1002/mds.29525
Abstrakt: 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.
Methods: 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.
(© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
Externí odkaz: