دورية أكاديمية
Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons
| العنوان: | Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons |
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| المؤلفون: | 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 |
| المصدر: | Movement disorders : official journal of the Movement Disorder Society (2023) |
| سنة النشر: | 2023 |
| المجموعة: | University of Luxembourg: ORBilu - Open Repository and Bibliography |
| مصطلحات موضوعية: | Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | peer reviewed ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0885-3185 |
| العلاقة: | https://doi.org/10.1002/mds.29525Test; FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald; urn:issn:0885-3185; https://orbilu.uni.lu/handle/10993/55633Test; info:hdl:10993/55633; https://orbilu.uni.lu/bitstream/10993/55633/1/Movement%20Disorders%20-%202023%20-%20Grossmann%20-%20Mitochondria%20Endoplasmic%20Reticulum%20Contact%20Sites%20Dynamics%20and%20Calcium%20Homeostasis.pdfTest; scopus-id:2-s2.0-85165304731; info:pmid:37449534 |
| DOI: | 10.1002/mds.29525 |
| الإتاحة: | https://doi.org/10.1002/mds.29525Test https://orbilu.uni.lu/handle/10993/55633Test https://orbilu.uni.lu/bitstream/10993/55633/1/Movement%20Disorders%20-%202023%20-%20Grossmann%20-%20Mitochondria%20Endoplasmic%20Reticulum%20Contact%20Sites%20Dynamics%20and%20Calcium%20Homeostasis.pdfTest |
| حقوق: | open access ; http://purl.org/coar/access_right/c_abf2Test ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.18D467DC |
| قاعدة البيانات: | BASE |
| تدمد: | 08853185 |
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| DOI: | 10.1002/mds.29525 |